chr6-2765749-C-T

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

1
3
15

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]
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]

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
WRNIP1NM_020135.3 linkc.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 Appris UniProt
WRNIP1ENST00000380773.9 linkc.127C>T p.His43Tyr missense_variant Exon 1 of 7 1 NM_020135.3 ENSP00000370150.4 Q96S55-1
WRNIP1ENST00000618555.4 linkc.127C>T p.His43Tyr missense_variant Exon 1 of 7 1 ENSP00000477551.1 Q96S55-1
WRNIP1ENST00000380771.8 linkc.127C>T p.His43Tyr missense_variant Exon 1 of 7 1 ENSP00000370148.4 Q96S55-2
MYLK4ENST00000698899.1 linkc.56+4309G>A intron_variant Intron 1 of 12 ENSP00000514016.1 A0A8V8TMV3

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151540
Hom.:
0
Cov.:
32
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:
4
AN:
143330
Hom.:
0
AF XY:
0.0000243
AC XY:
2
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:
37
AN:
1350856
Hom.:
0
Cov.:
30
AF XY:
0.0000209
AC XY:
14
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:
3
AN:
151540
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
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:
2

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
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
T;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.62
.;T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.078
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.55
N;N;N
PrimateAI
Pathogenic
0.90
D
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
T
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.

Other links and lift over

dbSNP: rs781540327; hg19: chr6-2765983; API