dbSNP rs139768159: INVS:p.His935Tyr (chr9-100296933-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014425.5(INVS):c.2803C>T(p.His935Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,614,000 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H935Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 14 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.712

Publications

6 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007744968).

BP6

Variant 9-100296933-C-T is Benign according to our data. Variant chr9-100296933-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215514.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (355/152254) while in subpopulation NFE AF = 0.00378 (257/68012). AF 95% confidence interval is 0.0034. There are 0 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014425.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INVS	NM_014425.5	MANE Select	c.2803C>T	p.His935Tyr	missense	Exon 15 of 17	NP_055240.2
INVS	NM_001318381.2		c.2515C>T	p.His839Tyr	missense	Exon 16 of 18	NP_001305310.1
INVS	NM_001318382.2		c.1825C>T	p.His609Tyr	missense	Exon 15 of 17	NP_001305311.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INVS	ENST00000262457.7	TSL:1 MANE Select	c.2803C>T	p.His935Tyr	missense	Exon 15 of 17	ENSP00000262457.2	Q9Y283-1
INVS	ENST00000885857.1		c.2803C>T	p.His935Tyr	missense	Exon 16 of 18	ENSP00000555916.1
INVS	ENST00000885859.1		c.2803C>T	p.His935Tyr	missense	Exon 16 of 18	ENSP00000555918.1

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

355

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00252

AC:

632

AN:

251282

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00285

AC:

4167

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2049

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00132

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00336

AC:

290

AN:

86230

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00317

AC:

3526

AN:

1111912

Other (OTH)

AF:

0.00270

AC:

163

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00233

AC:

355

AN:

152254

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41554

American (AMR)

AF:

0.00216

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00311

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00378

AC:

257

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

101

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:

0.00282

Hom.:

Bravo

AF:

0.00200

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00263

AC:

319

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00397

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Infantile nephronophthisis (1)

Nephronophthisis (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

M_CAP

Benign

0.0088

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

0.71

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.0

REVEL

Benign

0.051

Sift

Uncertain

0.014

Sift4G

Uncertain

0.051

Polyphen

0.52

Vest4

0.26

MVP

0.63

MPC

0.54

ClinPred

0.020

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.081

Mutation Taster

=86/14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over