rs376586707

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014714.4(IFT140):c.2399+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,066 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

IFT140
NM_014714.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-1557934-C-A is Pathogenic according to our data. Variant chr16-1557934-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 31680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1557934-C-A is described in Lovd as [Pathogenic]. Variant chr16-1557934-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.2399+1G>T		splice_donor_variant, intron_variant		ENST00000426508.7	NP_055529.2	Q96RY7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7 link	c.2399+1G>T		splice_donor_variant, intron_variant		5	NM_014714.4	ENSP00000406012.2		Q96RY7-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251478

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135908

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000319

AC:

466

AN:

1460894

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000411

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 80

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 11, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2013	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2021	DNA sequence analysis of the IFT140 gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2399+1G>T. This sequence change is predicted to affect mRNA splicing and is likely to result in an absent or truncated protein. It has been described in the gnomAD database in the non-Finnish European subpopulation with a low frequency of 0.012% only (dbSNP rs376586707). This sequence change has been previously described in the compound heterozygous state in family and individuals with IFT140-related disorders (PMIDs: 22503633, 26968735, 23418020). Collectively, this evidence indicates that the c.2399+1G>T change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed with a second variant on the opposite allele (in trans) in patients with Mainzer-Saldino syndrome or isolated retinal dystrophy in the published literature (Schmidts et al., 2013; Hull et al., 2016); This variant is associated with the following publications: (PMID: 31397098, 26968735, 28724397, 22503633, 29688594, 31980526, 31589614, 32037395, 23418020) -

Saldino-Mainzer syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change affects a donor splice site in intron 19 of the IFT140 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant is present in population databases (rs376586707, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with IFT140-related conditions (PMID: 22503633, 23418020, 26968735). ClinVar contains an entry for this variant (Variation ID: 31680). 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. -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -

Polycystic kidney disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 28, 2023

Criteria applied: PVS1,PS4_MOD -

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 01, 2024

- -

Autosomal dominant polycystic kidney disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

This sequence change in IFT140 occurs within the canonical splice donor site of intron 19. It is predicted to cause native donor site loss and cryptic donor creation leading to a one bp deletion resulting in a frameshift (exon 19/31) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 22282595, 34890546). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.04% (463/1,179,776 alleles) in the European (non-Finnish) population. This variant has been reported as a common cause of IFT140-related polycystic kidney disease (PKD) with a distinctive monoallelic phenotype of mild PKD with large cysts, limited kidney insufficiency, and few liver cysts (PMID: 34890546). The variant has been reported to segregate with PKD in multiple families (PMID: 34890546). This variant has been detected as compound heterozygous with a second pathogenic variant in at least two individuals with a ciliopathy phenotype (PMID: 22503633). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM3. -

IFT140-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The IFT140 c.2399+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant along with another IFT140 variant has been reported to be causative for Mainzer-Saldino syndrome and Jeune syndrome (Perrault et al. 2012. PubMed ID: 22503633; Schmidts et al. 2013. PubMed ID: 23418020). It has also been reported along with a missense IFT140 variant in two siblings with retinal dystrophy (Hull et al. 2016. PubMed ID: 26968735). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt consensus splice donor sites in IFT140 are expected to be pathogenic. Of note, monoallelic IFT140 loss-of-function pathogenic variants have been reported to cause the autosomal dominant polycystic kidney-spectrum phenotype and this splicing variant is among the pathogenic changes found in this study (Senum et al. 2022. PubMed ID: 34890546). This variant is interpreted as pathogenic for both autosomal recessive and autosomal dominant IFT140-related disorders. -

Renal cyst

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 09, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 80 (MIM#617781), short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920), and cystic kidney disease (MONDO#0002473), IFT140-related. (I) 0108 - This gene is associated with both recessive and dominant disease. Retinitis pigmentosa 80 (MIM#617781) and short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) are inherited in an autosomal recessive manner, while cystic kidney disease (MONDO#0002473), IFT140-related is inherited in an autosomal dominant manner (OMIM, PMID: 34890546) . (I) 0112 - The dominant condition associated with this gene may have incomplete penetrance. Parents of children with short-rib thoracic dysplasia 9 with or without polydactyly, who carry a single pathogenic variant that has also previously been associated with the dominant cystic kidney disease phenotype, have been reported as unaffected (PMID: 34890546). However these parents weren't specifically assessed for cystic kidney disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (14 heterozygote, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar and observed as compound heterozygous in several individuals with autosomal recessive retinitis pigemntosa, Jeune syndrome or Mainzer-Saldino syndrome (PMIDs: 22503633, 26968735, 23418020). This variant has also been observed as heterozygous in multiple individuals affected with autosomal dominant cystic kidney disease (PMID: 34890546). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 2

DS_DL_spliceai

1.0

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over