rs116314059

Positions:

chr9-100284460-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014425.5(INVS):c.1925A>G(p.Lys642Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,614,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 2 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.06

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008226305).

BP6

Variant 9-100284460-A-G is Benign according to our data. Variant chr9-100284460-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000696 (106/152358) while in subpopulation AFR AF= 0.00245 (102/41596). AF 95% confidence interval is 0.00207. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
INVS	NM_014425.5 linkuse as main transcript	c.1925A>G	p.Lys642Arg	missense_variant	13/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2 linkuse as main transcript	c.1637A>G	p.Lys546Arg	missense_variant	14/18		NP_001305310.1
INVS	NM_001318382.2 linkuse as main transcript	c.947A>G	p.Lys316Arg	missense_variant	13/17		NP_001305311.1
INVS	NR_134606.2 linkuse as main transcript	n.2123A>G		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.1925A>G	p.Lys642Arg	missense_variant	13/17	1	NM_014425.5	ENSP00000262457	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.1925A>G	p.Lys642Arg	missense_variant	13/18	5		ENSP00000262456	P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000478

GnomAD3 exomes

AF:

0.000184

AC:

AN:

250404

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00267

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00275

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152358

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.000196

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:

0.000473

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.000797

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2018	- -

INVS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nephronophthisis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.5

DANN

Benign

0.95

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.029

Sift

Benign

0.18

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.015

B;P

Vest4

0.12

MVP

0.52

MPC

0.26

ClinPred

0.020

GERP RS

3.2

Varity_R

0.028

gMVP

0.14

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