dbSNP rs776806803: WRNIP1:p.Leu12Ile (chr6-2765656-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020135.3(WRNIP1):c.34C>A(p.Leu12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L12F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

WRNIP1
NM_020135.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41185582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRNIP1	NM_020135.3 link	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 7	ENST00000380773.9	NP_064520.2	Q96S55-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRNIP1	ENST00000380773.9 link	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 7	1	NM_020135.3	ENSP00000370150.4	Q96S55-1
WRNIP1	ENST00000618555.4 link	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 7	1		ENSP00000477551.1	Q96S55-1
WRNIP1	ENST00000380771.8 link	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 7	1		ENSP00000370148.4	Q96S55-2
MYLK4	ENST00000698899.1 link	c.56+4402G>T		intron_variant	Intron 1 of 12			ENSP00000514016.1	A0A8V8TMV3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395258

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694668

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.20e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

T;.;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.64

.;T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.14

N;N;.

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.38

MutPred

0.13

Loss of disorder (P = 0.0915);Loss of disorder (P = 0.0915);Loss of disorder (P = 0.0915);

MVP

0.068

MPC

0.38

ClinPred

0.84

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.38

gMVP

0.19

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over