rs556958354

Variant names:

• chr8-31085193-G-A
• rs556958354
• NM_000553.6:c.1378G>A
• WRN p.Asp460Asn

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000553.6(WRN):​c.1378G>A​(p.Asp460Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,612,638 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. D460G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.22
• Publications: 1 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• osteosarcoma

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053675175).
• BP6: Variant 8-31085193-G-A is Benign according to our data. Variant chr8-31085193-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458382.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000137 (200/1460774) while in subpopulation SAS AF = 0.00206 (178/86222). AF 95% confidence interval is 0.00182. There are 1 homozygotes in GnomAdExome4. There are 143 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.1378G>A	p.Asp460Asn	missense	Exon 11 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.1378G>A	p.Asp460Asn	missense	Exon 11 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.1378G>A	p.Asp460Asn	missense	Exon 11 of 35	ENSP00000636235.1
	WRN	ENST00000860283.1		c.1378G>A	p.Asp460Asn	missense	Exon 11 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151750 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000378 AC: 95 AN: 251020 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1460774 Hom.: 1 Cov.: 30 AF XY: 0.000197 AC XY: 143 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39490

South Asian (SAS) AF: 0.00206 AC: 178 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111342

Other (OTH) AF: 0.000166 AC: 10 AN: 60348

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151864 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4802

European-Finnish (FIN) AF: 0.0000955 AC: 1 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Werner syndrome (2)
-	-	1	Wiskott-Aldrich syndrome (1)
-	-	1	WRN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.31	T
Sift4G	Benign	0.43	T
Varity_R		0.032
gMVP		0.29
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs556958354;

hg19: chr8-30942709;

COSMIC: COSV53308130;

COSMIC: COSV53308130;