chr8-31154674-G-A

Variant names:

• chr8-31154674-G-A
• rs147117969
• NM_000553.6:c.3738G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000553.6(WRN):​c.3738G>A​(p.Leu1246Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1246L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0950
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-31154674-G-A is Benign according to our data. Variant chr8-31154674-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238161.
• BP7: Synonymous conserved (PhyloP=-0.095 with no splicing effect.

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.3738G>A	p.Leu1246Leu	synonymous	Exon 32 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.3738G>A	p.Leu1246Leu	synonymous	Exon 32 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.2371G>A		non_coding_transcript_exon	Exon 20 of 23
	WRN	ENST00000966176.1		c.3753G>A	p.Leu1251Leu	synonymous	Exon 32 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000322 AC: 81 AN: 251226 AF XY: 0.000287

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000511

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000552 AC: 806 AN: 1461318 Hom.: 0 Cov.: 30 AF XY: 0.000524 AC XY: 381 AN XY: 726972

African (AFR) AF: 0.000837 AC: 28 AN: 33462

American (AMR) AF: 0.0000895 AC: 4 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000634 AC: 705 AN: 1111708

Other (OTH) AF: 0.000480 AC: 29 AN: 60364

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74378

African (AFR) AF: 0.000722 AC: 30 AN: 41532

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.000389

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Werner syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		-0.095
Mutation Taster		=100/0	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: rs147117969; hg19: chr8-31012190;