chr8-31167182-C-G

Variant names:

• chr8-31167182-C-G
• rs1203710521
• NM_000553.6:c.4143C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000553.6(WRN):​c.4143C>G​(p.Ile1381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1381I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000253961 (HGNC:58431):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05045271).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. 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
	WRN	NM_000553.6	MANE Select	c.4143C>G	p.Ile1381Met	missense	Exon 34 of 35	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.4143C>G	p.Ile1381Met	missense	Exon 34 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.2776C>G		non_coding_transcript_exon	Exon 22 of 23
	WRN	ENST00000966176.1		c.4158C>G	p.Ile1386Met	missense	Exon 34 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Werner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.45
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.089
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.057		Gain of catalytic residue at I1381 (P = 0.1148)
MVP		0.36
MPC		0.076
ClinPred		0.016	T
GERP RS		1.4
Varity_R		0.037
gMVP		0.14
Mutation Taster		=98/2	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: rs1203710521; hg19: chr8-31024698; COSMIC: COSV53307709;