rs76868679

Positions:

chr9-100292659-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014425.5(INVS):c.2402G>A(p.Gly801Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,144 control chromosomes in the GnomAD database, including 1,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 98 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1209 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.760

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002002865).

BP6

Variant 9-100292659-G-A is Benign according to our data. Variant chr9-100292659-G-A is described in ClinVar as [Benign]. Clinvar id is 167195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100292659-G-A is described in Lovd as [Benign]. Variant chr9-100292659-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
INVS	NM_014425.5 linkuse as main transcript	c.2402G>A	p.Gly801Glu	missense_variant	14/17	ENST00000262457.7
INVS	NM_001318381.2 linkuse as main transcript	c.2114G>A	p.Gly705Glu	missense_variant	15/18
INVS	NM_001318382.2 linkuse as main transcript	c.1424G>A	p.Gly475Glu	missense_variant	14/17
INVS	NR_134606.2 linkuse as main transcript	n.2551G>A		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.2402G>A	p.Gly801Glu	missense_variant	14/17	1	NM_014425.5	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.2179+223G>A		intron_variant		5		P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.0279

AC:

4249

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00821

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0275

AC:

6860

AN:

249112

Hom.:

145

AF XY:

0.0278

AC XY:

3751

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0240

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00467

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0438

Gnomad OTH exome

AF:

0.0335

GnomAD4 exome

AF:

0.0386

AC:

56400

AN:

1461868

Hom.:

1209

Cov.:

AF XY:

0.0378

AC XY:

27524

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00624

Gnomad4 AMR exome

AF:

0.0254

Gnomad4 ASJ exome

AF:

0.0237

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00547

Gnomad4 FIN exome

AF:

0.0226

Gnomad4 NFE exome

AF:

0.0452

Gnomad4 OTH exome

AF:

0.0351

GnomAD4 genome

AF:

0.0279

AC:

4250

AN:

152276

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1989

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00821

Gnomad4 AMR

AF:

0.0337

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0192

Gnomad4 NFE

AF:

0.0426

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0399

Hom.:

218

Bravo

AF:

0.0293

TwinsUK

AF:

0.0431

AC:

160

ALSPAC

AF:

0.0477

AC:

184

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0414

AC:

356

ExAC

AF:

0.0276

AC:

3356

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0459

EpiControl

AF:

0.0445

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2019

- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2020

- -

Infantile nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.13

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.33

REVEL

Benign

0.042

Sift

Benign

1.0

Sift4G

Benign

0.54

Polyphen

0.0070

Vest4

0.014

MPC

0.29

ClinPred

0.0090

GERP RS

0.43

Varity_R

0.025

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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