rs34477820

Variant names:

• chr8-31058542-A-G
• rs34477820
• NM_000553.6:c.95A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-31058542-A-G
• chr8-31058542-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000298139.7(WRN):​c.95A>G​(p.Lys32Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00386 in 1,613,424 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K32E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: WRN ENST00000298139.7 missense, splice_region
• Scores: Splicing: ADA: 0.9915
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 5.79
• Publications: 23 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048146844).
• BP6: Variant 8-31058542-A-G is Benign according to our data. Variant chr8-31058542-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135423.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (457/152366) while in subpopulation NFE AF = 0.00541 (368/68036). AF 95% confidence interval is 0.00495. There are 1 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000298139.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.95A>G	p.Lys32Arg	missense splice_region	Exon 2 of 35	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.95A>G	p.Lys32Arg	missense splice_region	Exon 2 of 35	ENSP00000298139.5
	WRN	ENST00000650667.1		n.95A>G		splice_region non_coding_transcript_exon	Exon 2 of 34	ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00305 AC: 764 AN: 250438 AF XY: 0.00307

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000787

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00395 AC: 5766 AN: 1461058 Hom.: 19 Cov.: 30 AF XY: 0.00396 AC XY: 2877 AN XY: 726816

African (AFR) AF: 0.000658 AC: 22 AN: 33450

American (AMR) AF: 0.00179 AC: 80 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26124

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.000859 AC: 74 AN: 86176

European-Finnish (FIN) AF: 0.00135 AC: 72 AN: 53378

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5750

European-Non Finnish (NFE) AF: 0.00478 AC: 5313 AN: 1111492

Other (OTH) AF: 0.00310 AC: 187 AN: 60360

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74514

African (AFR) AF: 0.000793 AC: 33 AN: 41590

American (AMR) AF: 0.00268 AC: 41 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00434 Hom.: 5

Bravo AF: 0.00286

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00358 AC: 435

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (3)
-	1	1	Werner syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.020	D
Polyphen		0.70	P
Vest4		0.21
MVP		0.75
MPC		0.28
ClinPred		0.031	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.52
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.060		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: rs34477820; hg19: chr8-30916058; COSMIC: COSV99035806;