9-100240169-C-T

Position:

chr9-100240169-C-T

Variant summary

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

The NM_014425.5(INVS):c.725C>T(p.Ser242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,613,908 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 38 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.91

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:

INVS (HGNC:):

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=0.015121937).

BP6

Variant 9-100240169-C-T is Benign according to our data. Variant chr9-100240169-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100240169-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0047 (716/152206) while in subpopulation NFE AF= 0.00652 (443/67996). AF 95% confidence interval is 0.00601. There are 4 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5 linkuse as main transcript	c.725C>T	p.Ser242Leu	missense_variant	6/17	ENST00000262457.7	NP_055240.2	Q9Y283-1A0A024R153
INVS	NM_001318381.2 linkuse as main transcript	c.437C>T	p.Ser146Leu	missense_variant	7/18		NP_001305310.1	Q2M1I4
INVS	NM_001318382.2 linkuse as main transcript	c.-265C>T		5_prime_UTR_variant	6/17		NP_001305311.1
INVS	NR_134606.2 linkuse as main transcript	n.923C>T		non_coding_transcript_exon_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.725C>T	p.Ser242Leu	missense_variant	6/17	1	NM_014425.5	ENSP00000262457.2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.725C>T	p.Ser242Leu	missense_variant	6/18	5		ENSP00000262456.2	Q9Y283-2
INVS	ENST00000460636.2 linkuse as main transcript	n.*43C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

716

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00651

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00467

AC:

1173

AN:

251440

Hom.:

AF XY:

0.00461

AC XY:

626

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.00636

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00571

AC:

8351

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

4048

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00391

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.00651

Gnomad4 OTH exome

AF:

0.00454

GnomAD4 genome

AF:

0.00470

AC:

716

AN:

152206

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

368

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.00652

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00561

Hom.:

Bravo

AF:

0.00401

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00456

AC:

553

EpiCase

AF:

0.00523

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 25, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	INVS: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Infantile nephronophthisis

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.7

L;L

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.98

D;D

Vest4

0.85

MVP

0.90

MPC

0.78

ClinPred

0.017

GERP RS

5.6

Varity_R

0.39

gMVP

0.37

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