rs147452898

Variant summary

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

The NM_014425.5(INVS):c.1948G>C(p.Ala650Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,614,130 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A650A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 25 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.716

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=0.009577215).

BP6

Variant 9-100284483-G-C is Benign according to our data. Variant chr9-100284483-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 95596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100284483-G-C is described in Lovd as [Likely_benign]. Variant chr9-100284483-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00375 (571/152360) while in subpopulation NFE AF= 0.00404 (275/68036). AF 95% confidence interval is 0.00365. There are 4 homozygotes in gnomad4. There are 309 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
INVS	NM_014425.5 linkuse as main transcript	c.1948G>C	p.Ala650Pro	missense_variant	13/17	ENST00000262457.7
INVS	NM_001318381.2 linkuse as main transcript	c.1660G>C	p.Ala554Pro	missense_variant	14/18
INVS	NM_001318382.2 linkuse as main transcript	c.970G>C	p.Ala324Pro	missense_variant	13/17
INVS	NR_134606.2 linkuse as main transcript	n.2146G>C		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.1948G>C	p.Ala650Pro	missense_variant	13/17	1	NM_014425.5	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.1948G>C	p.Ala650Pro	missense_variant	13/18	5		P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00404

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00399

AC:

998

AN:

250398

Hom.:

AF XY:

0.00391

AC XY:

530

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00425

AC:

6217

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

2997

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.0188

Gnomad4 NFE exome

AF:

0.00440

Gnomad4 OTH exome

AF:

0.00361

GnomAD4 genome

AF:

0.00375

AC:

571

AN:

152360

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000817

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.00404

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00330

AC:

400

EpiCase

AF:

0.00344

EpiControl

AF:

0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile nephronophthisis

Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 03, 2013

- -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

INVS: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0096

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.23

Sift

Benign

0.076

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.17

B;P

Vest4

0.19

MVP

0.37

MPC

0.46

ClinPred

0.011

GERP RS

-2.3

Varity_R

0.084

gMVP

0.15

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