rs1346044

Variant names:

• chr8-31167138-T-C
• rs1346044
• NM_000553.6:c.4099T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-31167138-T-C
• chr8-31167138-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.4099T>C​(p.Cys1367Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,060 control chromosomes in the GnomAD database, including 50,791 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1367G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4075 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46716 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.253
• Publications: 120 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

ENSG00000253961 (HGNC:58431):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015725493).
• BP6: Variant 8-31167138-T-C is Benign according to our data. Variant chr8-31167138-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

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.4099T>C	p.Cys1367Arg	missense	Exon 34 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.4099T>C	p.Cys1367Arg	missense	Exon 34 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.2732T>C		non_coding_transcript_exon	Exon 22 of 23
	WRN	ENST00000966176.1		c.4114T>C	p.Cys1372Arg	missense	Exon 34 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34263 AN: 151888 Hom.: 4073 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.238 AC: 59621 AN: 250952 AF XY: 0.242

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.249 AC: 363501 AN: 1461054 Hom.: 46716 Cov.: 36 AF XY: 0.250 AC XY: 182066 AN XY: 726832

African (AFR) AF: 0.161 AC: 5390 AN: 33450

American (AMR) AF: 0.195 AC: 8707 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5419 AN: 26118

East Asian (EAS) AF: 0.0893 AC: 3543 AN: 39666

South Asian (SAS) AF: 0.277 AC: 23911 AN: 86228

European-Finnish (FIN) AF: 0.293 AC: 15655 AN: 53390

Middle Eastern (MID) AF: 0.234 AC: 1348 AN: 5766

European-Non Finnish (NFE) AF: 0.257 AC: 285131 AN: 1111446

Other (OTH) AF: 0.239 AC: 14397 AN: 60348

GnomAD4 genome AF: 0.226 AC: 34282 AN: 152006 Hom.: 4075 Cov.: 32 AF XY: 0.226 AC XY: 16763 AN XY: 74306

African (AFR) AF: 0.163 AC: 6766 AN: 41492

American (AMR) AF: 0.197 AC: 3009 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3470

East Asian (EAS) AF: 0.114 AC: 586 AN: 5162

South Asian (SAS) AF: 0.288 AC: 1387 AN: 4820

European-Finnish (FIN) AF: 0.296 AC: 3126 AN: 10568

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18007 AN: 67936

Other (OTH) AF: 0.223 AC: 472 AN: 2112

Alfa AF: 0.245 Hom.: 23108

Bravo AF: 0.211

TwinsUK AF: 0.249 AC: 922

ALSPAC AF: 0.250 AC: 964

ESP6500AA AF: 0.172 AC: 757

ESP6500EA AF: 0.256 AC: 2200

ExAC AF: 0.241 AC: 29284

Asia WGS AF: 0.182 AC: 633 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.252

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	5	Werner syndrome (5)
-	-	2	not provided (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.25
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.070
Sift	Benign	0.035	D
Sift4G	Benign	0.095	T
Polyphen		0.74	P
Vest4		0.12
MPC		0.21
ClinPred		0.014	T
GERP RS		2.5
Varity_R		0.37
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1346044; hg19: chr8-31024654; COSMIC: COSV53296936; COSMIC: COSV53296936;