8-31043374-A-G

Variant names:

• chr8-31043374-A-G
• rs4733220
• NM_000553.6:c.-77+9401A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):​c.-77+9401A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 151,984 control chromosomes in the GnomAD database, including 20,514 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20514 hom., cov: 31)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 14 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• osteosarcoma

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.-77+9401A>G		intron_variant	Intron 1 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.-77+9401A>G		intron_variant	Intron 1 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000650667.1	n.-77+9401A>G		intron_variant	Intron 1 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76178 AN: 151866 Hom.: 20508 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.510

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.501 AC: 76192 AN: 151984 Hom.: 20514 Cov.: 31 AF XY: 0.503 AC XY: 37373 AN XY: 74268

African (AFR) AF: 0.294 AC: 12195 AN: 41462

American (AMR) AF: 0.553 AC: 8442 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2333 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3064 AN: 5152

South Asian (SAS) AF: 0.463 AC: 2224 AN: 4804

European-Finnish (FIN) AF: 0.594 AC: 6270 AN: 10552

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39822 AN: 67950

Other (OTH) AF: 0.512 AC: 1082 AN: 2112

Alfa AF: 0.558 Hom.: 107789

Bravo AF: 0.492

Asia WGS AF: 0.522 AC: 1815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.4
DANN	Benign	0.62
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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: rs4733220; hg19: chr8-30900890;