rs769121831

Variant names:

• chr8-31154639-A-C
• rs769121831
• NM_000553.6:c.3703A>C

Your query was ambiguous. Multiple possible variants found:

• chr8-31154639-A-C
• chr8-31154639-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000553.6(WRN):​c.3703A>C​(p.Ser1235Arg) 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. 15/21 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)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87

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]

ACMG classification

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=0.09361282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.3703A>C	p.Ser1235Arg	missense_variant	Exon 32 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3703A>C	p.Ser1235Arg	missense_variant	Exon 32 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.2336A>C		non_coding_transcript_exon_variant	Exon 20 of 23	1
WRN	ENST00000650667.1	n.*3317A>C		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*3317A>C		3_prime_UTR_variant	Exon 31 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249940 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

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 Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.057
Sift	Benign	0.13	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.20		Loss of glycosylation at S1235 (P = 0.0321);
MVP		0.55
MPC		0.072
ClinPred		0.22	T
GERP RS		5.4
Varity_R		0.24
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769121831; hg19: chr8-31012155;