rs1257404494

Variant names:

• chr8-31081003-G-A
• NM_000553.6:c.976G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31081003-G-A
• chr8-31081003-G-T

Variant summary

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

The NM_000553.6(WRN):​c.976G>A​(p.Gly326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.614

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=0.10609087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.976G>A	p.Gly326Arg	missense_variant	Exon 9 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.976G>A	p.Gly326Arg	missense_variant	Exon 9 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1	c.271G>A	p.Gly91Arg	missense_variant	Exon 3 of 4			ENSP00000498779.1
WRN	ENST00000650667.1	n.*590G>A		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*590G>A		3_prime_UTR_variant	Exon 8 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.097
Sift	Benign	0.13	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.33		Gain of catalytic residue at G326 (P = 0.0295);
MVP		0.43
MPC		0.23
ClinPred		0.65	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-30938519;