9-100284591-A-T

Position:

• chr9-100284591-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014425.5(INVS):​c.2056A>T​(p.Arg686*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: INVS NM_014425.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.82

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 (HGNC:):

ACMG classification

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 9-100284591-A-T is Pathogenic according to our data. Variant chr9-100284591-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 531629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.2056A>T	p.Arg686*	stop_gained	13/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.1768A>T	p.Arg590*	stop_gained	14/18		NP_001305310.1
INVS	NM_001318382.2	c.1078A>T	p.Arg360*	stop_gained	13/17		NP_001305311.1
INVS	NR_134606.2	n.2254A>T		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.2056A>T	p.Arg686*	stop_gained	13/17	1	NM_014425.5	ENSP00000262457.2
INVS	ENST00000262456.6	c.2056A>T	p.Arg686*	stop_gained	13/18	5		ENSP00000262456.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2017

This sequence change creates a premature translational stop signal (p.Arg686*) in the INVS gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with INVS-related disease. Loss-of-function variants in INVS are known to be pathogenic (PMID: 12872123). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.86
GERP RS		4.6

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

Other links and lift over

dbSNP: rs150001738; hg19: chr9-103046873;