16-1587961-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_014714.4(IFT140):c.874G>A(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

IFT140
NM_014714.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.55

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:

ENSG00000260989 (HGNC:):

ENSG00000260989 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

PP5

Variant 16-1587961-C-T is Pathogenic according to our data. Variant chr16-1587961-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1587961-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.874G>A	p.Val292Met	missense_variant	Exon 8 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.874G>A	p.Val292Met	missense_variant	Exon 8 of 31	5	NM_014714.4	ENSP00000406012.2	Q96RY7-1
IFT140	ENST00000439987.6 link	n.935G>A		non_coding_transcript_exon_variant	Exon 7 of 19	2
IFT140	ENST00000397417.6 link	n.329-3541G>A		intron_variant	Intron 3 of 23	5		ENSP00000380562.2	J3KPW0
ENSG00000260989	ENST00000563162.1 link	n.59+7376C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249478

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134878

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460968

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000363

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80

Pathogenic:1

Apr 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Saldino-Mainzer syndrome;C4518774:Joubert syndrome with Jeune asphyxiating thoracic dystrophy

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

- -

Saldino-Mainzer syndrome

Pathogenic:1

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Mar 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IFT140 c.874G>A (p.Val292Met) results in a conservative amino acid change located in the WD40/YVTN repeat-like-containing domain superfamily (IPR015943) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249478 control chromosomes (gnomAD). c.874G>A has been reported in the literature in multiple individuals affected with IFT140 related disorders (examples: Perrault_2012, Schmidts_2013, Dineiro_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 22503633, 23418020). ClinVar contains an entry for this variant (Variation ID: 97053). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.49

Sift

Benign

0.049

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.89

MVP

0.82

MPC

0.26

ClinPred

0.86

GERP RS

4.4

Varity_R

0.15

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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