rs150001738

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_014425.5(INVS):c.2056A>G(p.Arg686Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,613,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.82

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

INVS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04128748).

BP6

Variant 9-100284591-A-G is Benign according to our data. Variant chr9-100284591-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 500642.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152380) while in subpopulation NFE AF = 0.000676 (46/68038). AF 95% confidence interval is 0.00052. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5 link	c.2056A>G	p.Arg686Gly	missense_variant	Exon 13 of 17	ENST00000262457.7	NP_055240.2	Q9Y283-1A0A024R153
INVS	NM_001318381.2 link	c.1768A>G	p.Arg590Gly	missense_variant	Exon 14 of 18		NP_001305310.1	Q2M1I4
INVS	NM_001318382.2 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 13 of 17		NP_001305311.1
INVS	NR_134606.2 link	n.2254A>G		non_coding_transcript_exon_variant	Exon 13 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7 link	c.2056A>G	p.Arg686Gly	missense_variant	Exon 13 of 17	1	NM_014425.5	ENSP00000262457.2		Q9Y283-1
INVS	ENST00000262456.6 link	c.2056A>G	p.Arg686Gly	missense_variant	Exon 13 of 18	5		ENSP00000262456.2		Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000307

AC:

AN:

247418

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000434

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000528

AC:

771

AN:

1461098

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33466

American (AMR)

AF:

0.000425

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26098

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000929

AC:

AN:

86092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.000631

AC:

701

AN:

1111664

Other (OTH)

AF:

0.000530

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000348

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41600

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000355

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Infantile nephronophthisis

Uncertain:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

INVS-related disorder

Uncertain:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The INVS c.2056A>G variant is predicted to result in the amino acid substitution p.Arg686Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Nephronophthisis

Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 686 of the INVS protein (p.Arg686Gly). This variant is present in population databases (rs150001738, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with INVS-related conditions. ClinVar contains an entry for this variant (Variation ID: 500642). 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 tolerated. 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. -

not provided

Uncertain:1

Jan 11, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M

PhyloP100

1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0080

D;T

Sift4G

Uncertain

0.034

D;T

Polyphen

0.0020

B;P

Vest4

0.40

MVP

0.55

MPC

0.29

ClinPred

0.041

GERP RS

4.6

Varity_R

0.11

gMVP

0.12

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over