rs1554726564

chr9-100253068-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014425.5(INVS):c.1396G>A(p.Gly466Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.1396G>A	p.Gly466Arg	missense_variant	10/17	ENST00000262457.7
INVS	NM_001318381.2	c.1108G>A	p.Gly370Arg	missense_variant	11/18
INVS	NM_001318382.2	c.418G>A	p.Gly140Arg	missense_variant	10/17
INVS	NR_134606.2	n.1594G>A		non_coding_transcript_exon_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.1396G>A	p.Gly466Arg	missense_variant	10/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.1396G>A	p.Gly466Arg	missense_variant	10/18	5		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 462709). This variant has not been reported in the literature in individuals affected with INVS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 466 of the INVS protein (p.Gly466Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.26	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.029	D;T
Sift4G	Uncertain	0.037	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.57		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.87
MPC		0.92
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.52
gMVP		0.78

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: rs1554726564; hg19: chr9-103015350;