chr6-2765749-C-T

Variant names:

Variant summary

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

The NM_020135.3(WRNIP1):c.127C>T(p.His43Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,502,396 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

WRNIP1
NM_020135.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.317

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:

Genome browser will be placed here

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=0.0777013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRNIP1	NM_020135.3 link	c.127C>T	p.His43Tyr	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.127C>T	p.His43Tyr	missense_variant	Exon 1 of 7	1	NM_020135.3	ENSP00000370150.4	Q96S55-1
WRNIP1	ENST00000618555.4 link	c.127C>T	p.His43Tyr	missense_variant	Exon 1 of 7	1		ENSP00000477551.1	Q96S55-1
WRNIP1	ENST00000380771.8 link	c.127C>T	p.His43Tyr	missense_variant	Exon 1 of 7	1		ENSP00000370148.4	Q96S55-2
MYLK4	ENST00000698899.1 link	c.56+4309G>A		intron_variant	Intron 1 of 12			ENSP00000514016.1	A0A8V8TMV3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

143330

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

82318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000304

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1350856

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

671182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000715

Gnomad4 AMR exome

AF:

0.0000590

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:

0.0000301

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151540

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73992

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000176

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127C>T (p.H43Y) 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 127, causing the histidine (H) at amino acid position 43 to be replaced by a tyrosine (Y). 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

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.62

.;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.078

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.78

N;N;.

REVEL

Benign

0.036

Sift

Uncertain

0.0070

D;D;.

Sift4G

Benign

0.086

T;T;T

Polyphen

0.045

B;B;B

Vest4

0.22

MutPred

0.33

Loss of disorder (P = 0.0207);Loss of disorder (P = 0.0207);Loss of disorder (P = 0.0207);

MVP

0.11

MPC

0.23

ClinPred

0.048

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.17

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