Variant 6-2766065-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020135.3(WRNIP1):c.443C>T(p.Ala148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,293,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

WRNIP1
NM_020135.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.171

Variant links:

Genes affected

WRNIP1 (HGNC:20876): (WRN helicase interacting protein 1) Werner's syndrome is a rare autosomal recessive disorder characterized by accelerated aging that is caused by defects in the Werner syndrome ATP-dependent helicase gene (WRN). The protein encoded by this gene interacts with the exonuclease-containing N-terminal portion of the Werner protein. This protein has a ubiquitin-binding zinc-finger domain in the N-terminus, an ATPase domain, and two leucine zipper motifs in the C-terminus. It has sequence similarity to replication factor C family proteins and is conserved from E. coli to human. This protein likely accumulates at sites of DNA damage by interacting with polyubiquinated proteins and also binds to DNA polymerase delta and increases the initiation frequency of DNA polymerase delta-mediated DNA synthesis. This protein also interacts with nucleoporins at nuclear pore complexes. Two transcript variants encoding different isoforms have been isolated for this gene. [provided by RefSeq, Jul 2012]

WRNIP1 links:

MYLK4 (HGNC:27972): (myosin light chain kinase family member 4) Predicted to enable myosin light chain kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MYLK4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10791549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRNIP1	NM_020135.3 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	1/7	ENST00000380773.9	NP_064520.2	Q96S55-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRNIP1	ENST00000380773.9 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	1/7	1	NM_020135.3	ENSP00000370150.4		Q96S55-1

Frequencies

GnomAD3 genomes

AF:

0.000613

AC:

AN:

151720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1141670

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

548506

show subpopulations

Gnomad4 AFR exome

AF:

0.00130

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000313

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000619

AC:

AN:

151828

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00210

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000475

Bravo

AF:

0.000574

ExAC

AF:

0.0000790

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.443C>T (p.A148V) alteration is located in exon 1 (coding exon 1) of the WRNIP1 gene. This alteration results from a C to T substitution at nucleotide position 443, causing the alanine (A) at amino acid position 148 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.60

.;T;T

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.72

N;N;.

REVEL

Benign

0.043

Sift

Pathogenic

0.0

D;D;.

Sift4G

Benign

0.35

T;T;T

Polyphen

0.88

P;P;P

Vest4

0.24

MutPred

0.27

Gain of MoRF binding (P = 0.0893);Gain of MoRF binding (P = 0.0893);Gain of MoRF binding (P = 0.0893);

MVP

0.082

MPC

0.43

ClinPred

0.74

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.23

gMVP

0.18

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