9-100292952-C-T

Position:

chr9-100292952-C-T

Variant summary

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

The NM_014425.5(INVS):c.2695C>T(p.Arg899Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,612,784 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

INVS
NM_014425.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 3.26

Variant links:

Genes affected

INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]

INVS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 9-100292952-C-T is Pathogenic according to our data. Variant chr9-100292952-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100292952-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
INVS	NM_014425.5 linkuse as main transcript	c.2695C>T	p.Arg899Ter	stop_gained	14/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2 linkuse as main transcript	c.2407C>T	p.Arg803Ter	stop_gained	15/18		NP_001305310.1
INVS	NM_001318382.2 linkuse as main transcript	c.1717C>T	p.Arg573Ter	stop_gained	14/17		NP_001305311.1
INVS	NR_134606.2 linkuse as main transcript	n.2844C>T		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.2695C>T	p.Arg899Ter	stop_gained	14/17	1	NM_014425.5	ENSP00000262457	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.2185C>T	p.Arg729Ter	stop_gained	15/18	5		ENSP00000262456	P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251306

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1460652

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726364

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile nephronophthisis

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The INVS c.2695C>T (p.Arg899Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg899Ter variant has been reported in at least five studies in which it is found in a total of eight patients with nephronophthisis, including three in a homozygous state and five in a compound heterozygous state (Otto et al. 2003, Otto et al. 2008, Tory et al. 2009, Bellavia et al. 2010, Halbritter et al. 2013). Segregation analysis confirmed co-segregation with disease in an autosomal recessive inheritance pattern in one family with two affected siblings (Bellavia et al. 2010). The p.Arg899Ter variant was absent from 292 controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg899Ter variant is classified as pathogenic for nephronophthisis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 04, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 12872123, 21866095, 25525159] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -

Nephronophthisis

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change creates a premature translational stop signal (p.Arg899*) in the INVS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in INVS are known to be pathogenic (PMID: 12872123). This variant is present in population databases (rs200844390, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with nephronophthisis-associated ciliopathies (PMID: 12872123, 21866095). ClinVar contains an entry for this variant (Variation ID: 11962). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Nov 09, 2018	This individual is heterozygous for the c.2695C>T variant in the INVS gene. This variant creates a premature stop codon p.(Arg899*) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). The variant has been previously reported in multiple patients with nephronophthisis (Tory et al 2009 Kidney Int. 75(8):839-47; Otto et al 2003 Nat Genet. 34(4):413-20). This variant is considered to be a pathogenic according to the ACMG guidelines. (Evidence: PVS1, PM2, PM3). -

INVS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

The INVS c.2695C>T variant is predicted to result in premature protein termination (p.Arg899*). This variant has been reported in individuals with nephronophthisis (Otto et al. 2003. PubMed ID: 12872123; Chaki et al. 2011. PubMed ID: 21866095; Supplemental Data 1, Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-103055234-C-T). Nonsense variants in INVS are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18076122, 25525159, 20798123, 12872123, 23559409, 21866095, 31980526, 34426522, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

A;A;A

Vest4

0.89

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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