rs587776909

chr16-1520004-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_014714.4(IFT140):c.3916_3917insG(p.Ala1306GlyfsTer56) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,602,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1306A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

IFT140
NM_014714.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:4

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 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-1520004-G-GC is Pathogenic according to our data. Variant chr16-1520004-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 31684.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4 linkuse as main transcript	c.3916_3917insG	p.Ala1306GlyfsTer56	frameshift_variant	29/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7 linkuse as main transcript	c.3916_3917insG	p.Ala1306GlyfsTer56	frameshift_variant	29/31	5	NM_014714.4	P1	Q96RY7-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000830

AC:

AN:

240826

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130174

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.0000306

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1450176

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000610

Gnomad4 AMR exome

AF:

0.0000468

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Saldino-Mainzer syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 04, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 17, 2019	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant has been observed to segregate with Mainzer-Saldino in a family (PMID: 22503633). This variant is present in population databases (rs775537867, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Ala1306Glyfs*56) in the IFT140 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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