6-2765846-C-T

Position:

• chr6-2765846-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_020135.3(WRNIP1):​c.224C>T​(p.Ser75Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,250,926 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: WRNIP1 NM_020135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity WRIP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16699916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRNIP1	NM_020135.3	c.224C>T	p.Ser75Leu	missense_variant	1/7	ENST00000380773.9	NP_064520.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRNIP1	ENST00000380773.9	c.224C>T	p.Ser75Leu	missense_variant	1/7	1	NM_020135.3	ENSP00000370150.4
WRNIP1	ENST00000618555.4	c.224C>T	p.Ser75Leu	missense_variant	1/7	1		ENSP00000477551.1
WRNIP1	ENST00000380771.8	c.224C>T	p.Ser75Leu	missense_variant	1/7	1		ENSP00000370148.4
MYLK4	ENST00000698899.1	c.56+4212G>A		intron_variant				ENSP00000514016.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000165 AC: 1 AN: 60512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 35862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000967

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 24 AN: 1250926 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 11 AN XY: 614530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000495

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: 0.0000228

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.224C>T (p.S75L) 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 224, causing the serine (S) at amino acid position 75 to be replaced by a leucine (L). 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	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.78	.;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.0	N;N;.
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.0020	B;B;B
Vest4		0.35
MutPred		0.18		Loss of phosphorylation at S75 (P = 0.0011);Loss of phosphorylation at S75 (P = 0.0011);Loss of phosphorylation at S75 (P = 0.0011);
MVP		0.19
MPC		0.31
ClinPred		0.24	T
GERP RS		2.5
Varity_R		0.18
gMVP		0.26

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

Other links and lift over

dbSNP: rs1475038973; hg19: chr6-2766080;