6-2765656-C-G

Variant names:

• chr6-2765656-C-G
• rs776806803
• NM_020135.3:c.34C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020135.3(WRNIP1):​c.34C>G​(p.Leu12Val) 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. 13/22 in silico tools predict 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3797934).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020135.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRNIP1	NM_020135.3	MANE Select	c.34C>G	p.Leu12Val	missense	Exon 1 of 7	NP_064520.2
	WRNIP1	NM_130395.3		c.34C>G	p.Leu12Val	missense	Exon 1 of 7	NP_569079.1	Q96S55-2
	MYLK4	NM_001347872.2		c.56+4402G>C		intron	N/A	NP_001334801.1	A0A8V8TMV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRNIP1	ENST00000380773.9	TSL:1 MANE Select	c.34C>G	p.Leu12Val	missense	Exon 1 of 7	ENSP00000370150.4	Q96S55-1
	WRNIP1	ENST00000618555.4	TSL:1	c.34C>G	p.Leu12Val	missense	Exon 1 of 7	ENSP00000477551.1	Q96S55-1
	WRNIP1	ENST00000380771.8	TSL:1	c.34C>G	p.Leu12Val	missense	Exon 1 of 7	ENSP00000370148.4	Q96S55-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183164 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395258 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 694668

African (AFR) AF: 0.00 AC: 0 AN: 28810

American (AMR) AF: 0.00 AC: 0 AN: 39952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24282

East Asian (EAS) AF: 0.00 AC: 0 AN: 33090

South Asian (SAS) AF: 0.00 AC: 0 AN: 82628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087274

Other (OTH) AF: 0.00 AC: 0 AN: 57522

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.33
MutPred		0.099		Loss of helix (P = 0.0626)
MVP		0.082
MPC		0.36
ClinPred		0.49	T
GERP RS		3.7
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.33
gMVP		0.26
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs776806803; hg19: chr6-2765890;