rs41312220

Positions:

chr9-100240184-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014425.5(INVS):c.740A>G(p.Asn247Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00565 in 1,613,976 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 35 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.27

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=0.009686917).

BP6

Variant 9-100240184-A-G is Benign according to our data. Variant chr9-100240184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100240184-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00503 (765/152234) while in subpopulation NFE AF= 0.00768 (522/68006). AF 95% confidence interval is 0.00713. There are 1 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
INVS	NM_014425.5 linkuse as main transcript	c.740A>G	p.Asn247Ser	missense_variant	6/17	ENST00000262457.7
INVS	NM_001318381.2 linkuse as main transcript	c.452A>G	p.Asn151Ser	missense_variant	7/18
INVS	NM_001318382.2 linkuse as main transcript	c.-250A>G		5_prime_UTR_variant	6/17
INVS	NR_134606.2 linkuse as main transcript	n.938A>G		non_coding_transcript_exon_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.740A>G	p.Asn247Ser	missense_variant	6/17	1	NM_014425.5	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.740A>G	p.Asn247Ser	missense_variant	6/18	5		P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

765

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00315

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00767

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00481

AC:

1209

AN:

251430

Hom.:

AF XY:

0.00483

AC XY:

656

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00565

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.00696

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00571

AC:

8349

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

4154

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.00540

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.00525

GnomAD4 genome

AF:

0.00503

AC:

765

AN:

152234

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.00768

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00621

Hom.:

Bravo

AF:

0.00408

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00475

AC:

577

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 33131162) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	INVS: BS2 -

Infantile nephronophthisis

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

INVS-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2021

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

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

0.068

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.11

Sift

Benign

0.071

T;T

Sift4G

Benign

0.089

T;T

Polyphen

0.25

B;B

Vest4

0.38

MVP

0.72

MPC

0.36

ClinPred

0.034

GERP RS

5.6

Varity_R

0.17

gMVP

0.26

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