8-31141764-G-T

Variant names:

• chr8-31141764-G-T
• rs1801195
• NM_000553.6:c.3222G>T

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.3222G>T​(p.Leu1074Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,612,852 control chromosomes in the GnomAD database, including 166,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1074L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.46 (16580 hom., cov: 31)
  • Exomes 𝑓: 0.45 (149685 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.235
• Publications: 73 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=6.2455006E-6).
• BP6: Variant 8-31141764-G-T is Benign according to our data. Variant chr8-31141764-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 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.3222G>T	p.Leu1074Phe	missense	Exon 26 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.3222G>T	p.Leu1074Phe	missense	Exon 26 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1855G>T		non_coding_transcript_exon	Exon 14 of 23
	WRN	ENST00000966176.1		c.3237G>T	p.Leu1079Phe	missense	Exon 26 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70066 AN: 151798 Hom.: 16551 Cov.: 31

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.455 AC: 114051 AN: 250884 AF XY: 0.445

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.449 AC: 656181 AN: 1460936 Hom.: 149685 Cov.: 44 AF XY: 0.444 AC XY: 322859 AN XY: 726824

African (AFR) AF: 0.491 AC: 16437 AN: 33458

American (AMR) AF: 0.557 AC: 24883 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11605 AN: 26130

East Asian (EAS) AF: 0.606 AC: 24037 AN: 39680

South Asian (SAS) AF: 0.332 AC: 28601 AN: 86216

European-Finnish (FIN) AF: 0.364 AC: 19431 AN: 53384

Middle Eastern (MID) AF: 0.369 AC: 2078 AN: 5636

European-Non Finnish (NFE) AF: 0.452 AC: 501827 AN: 1111368

Other (OTH) AF: 0.452 AC: 27282 AN: 60358

GnomAD4 genome AF: 0.462 AC: 70148 AN: 151916 Hom.: 16580 Cov.: 31 AF XY: 0.457 AC XY: 33967 AN XY: 74246

African (AFR) AF: 0.486 AC: 20146 AN: 41416

American (AMR) AF: 0.544 AC: 8303 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1573 AN: 3466

East Asian (EAS) AF: 0.618 AC: 3189 AN: 5164

South Asian (SAS) AF: 0.319 AC: 1536 AN: 4810

European-Finnish (FIN) AF: 0.360 AC: 3791 AN: 10530

Middle Eastern (MID) AF: 0.483 AC: 140 AN: 290

European-Non Finnish (NFE) AF: 0.445 AC: 30235 AN: 67948

Other (OTH) AF: 0.464 AC: 978 AN: 2110

Alfa AF: 0.454 Hom.: 31162

Bravo AF: 0.481

TwinsUK AF: 0.463 AC: 1717

ALSPAC AF: 0.455 AC: 1754

ESP6500AA AF: 0.482 AC: 2124

ESP6500EA AF: 0.459 AC: 3949

ExAC AF: 0.449 AC: 54519

Asia WGS AF: 0.480 AC: 1665 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	4	Werner syndrome (4)
-	-	2	not provided (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.23
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.070	T
MetaRNN	Benign	0.0000063	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.23
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.023
Sift	Benign	0.76	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.0090
MutPred		0.29		Gain of methylation at K1073 (P = 0.0367)
MPC		0.069
ClinPred		0.0033	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.13
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: rs1801195; hg19: chr8-30999280; COSMIC: COSV53297644;