8-31111701-C-G

Variant names:

• chr8-31111701-C-G
• NM_000553.6:c.2175C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000553.6(WRN):​c.2175C>G​(p.Ile725Met) 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 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27207232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.2175C>G	p.Ile725Met	missense_variant	Exon 19 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.2175C>G	p.Ile725Met	missense_variant	Exon 19 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.808C>G		non_coding_transcript_exon_variant	Exon 7 of 23	1
WRN	ENST00000650667.1	n.*1789C>G		non_coding_transcript_exon_variant	Exon 18 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*1789C>G		3_prime_UTR_variant	Exon 18 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Benign	0.052	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.60	P
Vest4		0.44
MutPred		0.42		Gain of catalytic residue at I725 (P = 0.2454);
MVP		0.46
MPC		0.38
ClinPred		0.81	D
GERP RS		-3.5
Varity_R		0.12
gMVP		0.58

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: chr8-30969217;