rs3087414

Variant names:

• chr8-31142628-C-T
• rs3087414
• NM_000553.6:c.3236C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-31142628-C-T
• chr8-31142628-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000553.6(WRN):​c.3236C>T​(p.Ser1079Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,593,104 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1079T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (43 hom.)
• Consequence: WRN NM_000553.6 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.425
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028501153).
• BP6: Variant 8-31142628-C-T is Benign according to our data. Variant chr8-31142628-C-T is described in ClinVar as Benign. ClinVar VariationId is 130756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0147 (2233/152026) while in subpopulation AFR AF = 0.0487 (2018/41468). AF 95% confidence interval is 0.0469. There are 45 homozygotes in GnomAd4. There are 1059 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

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.3236C>T	p.Ser1079Leu	missense splice_region	Exon 27 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.3236C>T	p.Ser1079Leu	missense splice_region	Exon 27 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1869C>T		splice_region non_coding_transcript_exon	Exon 15 of 23
	WRN	ENST00000966176.1		c.3251C>T	p.Ser1084Leu	missense splice_region	Exon 27 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2224 AN: 151908 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00433 AC: 1057 AN: 243910 AF XY: 0.00343

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00201 AC: 2897 AN: 1441078 Hom.: 43 Cov.: 29 AF XY: 0.00176 AC XY: 1257 AN XY: 715890

African (AFR) AF: 0.0502 AC: 1648 AN: 32822

American (AMR) AF: 0.00497 AC: 214 AN: 43032

Ashkenazi Jewish (ASJ) AF: 0.00121 AC: 31 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39188

South Asian (SAS) AF: 0.0000994 AC: 8 AN: 80450

European-Finnish (FIN) AF: 0.000152 AC: 8 AN: 52692

Middle Eastern (MID) AF: 0.00622 AC: 35 AN: 5630

European-Non Finnish (NFE) AF: 0.000641 AC: 707 AN: 1102222

Other (OTH) AF: 0.00414 AC: 246 AN: 59446

GnomAD4 genome AF: 0.0147 AC: 2233 AN: 152026 Hom.: 45 Cov.: 32 AF XY: 0.0143 AC XY: 1059 AN XY: 74308

African (AFR) AF: 0.0487 AC: 2018 AN: 41468

American (AMR) AF: 0.00923 AC: 141 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

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

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67964

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00574 Hom.: 47

Bravo AF: 0.0166

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0430 AC: 189

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00492 AC: 597

Asia WGS AF: 0.00376 AC: 13 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Werner syndrome (4)
-	-	2	not provided (2)
-	-	1	not specified (2)
-	-	1	Wiskott-Aldrich syndrome (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	-0.66
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.041
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.41	B
Vest4		0.10
MVP		0.38
MPC		0.059
ClinPred		0.0024	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.28
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3087414; hg19: chr8-31000144; COSMIC: COSV53298491;