rs913325260

Variant names:

• chr8-31124522-G-T
• rs913325260
• NM_000553.6:c.2631G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-31124522-G-T
• chr8-31124522-G-A
• chr8-31124522-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000553.6(WRN):​c.2631G>T​(p.Arg877Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WRN NM_000553.6 missense, splice_region
• Scores: Splicing: ADA: 0.9432
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

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.2631G>T	p.Arg877Ser	missense splice_region	Exon 22 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.2631G>T	p.Arg877Ser	missense splice_region	Exon 22 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1264G>T		splice_region non_coding_transcript_exon	Exon 10 of 23
	WRN	ENST00000966176.1		c.2646G>T	p.Arg882Ser	missense splice_region	Exon 22 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Werner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.77
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.94	P
Vest4		0.52
MutPred		0.51		Loss of MoRF binding (P = 0.0305)
MVP		0.47
MPC		0.096
ClinPred		0.83	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.72
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.56		Position offset: 0

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

Other links and lift over

dbSNP: rs913325260; hg19: chr8-30982038;