16-1592176-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_014714.4(IFT140):c.634G>A(p.Gly212Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

IFT140
NM_014714.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.61

Publications

18 publications found

Variant links:

Genes affected

IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]

IFT140 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
IFT140-related recessive ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
short-rib thoracic dysplasia 9 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
retinitis pigmentosa 80
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFT140 links:

ENSG00000260989 (HGNC:):

ENSG00000260989 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-1592176-C-T is Pathogenic according to our data. Variant chr16-1592176-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.634G>A	p.Gly212Arg	missense_variant, splice_region_variant	Exon 6 of 31	ENST00000426508.7	NP_055529.2	Q96RY7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IFT140	ENST00000426508.7 link	c.634G>A	p.Gly212Arg	missense_variant, splice_region_variant	Exon 6 of 31	5	NM_014714.4	ENSP00000406012.2	Q96RY7-1
IFT140	ENST00000439987.6 link	n.695G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 19	2
IFT140	ENST00000397417.6 link	n.329-7756G>A		intron_variant	Intron 3 of 23	5		ENSP00000380562.2	J3KPW0
ENSG00000260989	ENST00000563162.1 link	n.59+11591C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251364

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1111990

Other (OTH)

AF:

0.000149

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Saldino-Mainzer syndrome

Pathogenic:5

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the IFT140 protein (p.Gly212Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201188361, gnomAD 0.009%). This missense change has been observed in individual(s) with Mainzer-Saldino syndrome, Jeune synrome, or Senior-Loken syndrome (PMID: 22503633, 28559085, 28724397). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31683). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IFT140 function (PMID: 22503633, 28724397). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2018

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 14, 2019

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 10, 2019

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The IFT140 c.634G>A (p.Gly212Arg) variant has been reported in two studies and was found in four probands, including one sibling-pair, one in a homozygous state and three in a compound heterozygous state (Perrault et al. 2012; Helm et al. 2017). One of these probands, who carried the splice-site mutation on the other allele, was clinically diagnosed with Jeune syndrome. Jeune syndrome has overlapping symptoms with Mainzer-Saldino syndrome with the additional phenotype of asphyxiating thoracic dystrophy. The p.Gly212Arg variant is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies of the p.Gly212Arg variant in retinal pigment epithelial cells showed changes to the cellular localization of the variant protein (Perrault et al. 2012). In vitro analysis in lymphocyte cells found that the p.Gly212Arg variant affected splicing of exon 6 (Helm et al. 2017). Based on the evidence, the p.Gly212Arg variant is classified as likely pathogenic for Mainzer-Saldino syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 04, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Apr 01, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Perrault et al., 2012; Helm et al., 2017); Variant impacting the last nucleotide of an exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 30924848, 29068549, 30773290, 28724397, 29688594, 28559085, 32371413, 28288023, 22503633, 31589614) -

Jul 15, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IFT140: PM3:Very Strong, PM2, PP3 -

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80

Pathogenic:2

Jan 31, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

[ACMG/AMP: PVS1, PS3, PM2, PM3, PP3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jeune thoracic dystrophy

Pathogenic:2

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Retinitis pigmentosa 80

Pathogenic:1

May 04, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal ciliopathy due to mutation in the retinitis pigmentosa-1 gene

Pathogenic:1

Jan 01, 2018

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

IFT140-related disorder

Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The IFT140 c.634G>A variant is predicted to result in the amino acid substitution p.Gly212Arg. This variant has been reported in multiple individuals with IFT140-related ciliopathy (for examples, see Perrault et al. 2012. PubMed ID: 22503633; Bayat. 2017. PubMed ID: 28288023). With a second pathogenic variant on the opposite chromosome (in trans), the variant was documented to be causative for Mainzer-Saldino Syndrome and Jeune Syndrome in an adult patient and a child patient, respectively (Perrault et al. 2012. PubMed: 22503633). It has also been found in the compound heterozygous state in an individual with cleft palate (Wilson et al. 2023. PubMed ID: 37010288). This variant has been shown to disrupt splicing in an in vivo model, leading to loss of function (Helm et al. 2017. PubMed ID: 28724397). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Nephronophthisis

Pathogenic:1

Oct 25, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This patient is heterozygous for a c.634G>A (p.Gly212Arg) in the IFT140 gene. This variant has been previously reported in conjunction with a second pathogenic IFT140 mutation in patients with Mainzer-Saldino syndrome (MSS) and Jeune syndrome .Functional studies have shown that this variant affects IFT140 cell localization and therefore this variant is considered to be pathogenic (Perrault et al. 2012, Am. J. Hum.Genet 90, 864-870). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.9

PhyloP100

7.6

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.93

MutPred

0.66

Loss of loop (P = 0.0603);

MVP

0.72

MPC

0.43

ClinPred

0.92

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.72

gMVP

0.84

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.61

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over