rs4987238

Variant names:

• chr8-31081176-G-C
• NM_000553.6:c.1149G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-31081176-G-C
• chr8-31081176-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000553.6(WRN):​c.1149G>C​(p.Leu383Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L383W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.233

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061977535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.1149G>C	p.Leu383Phe	missense_variant	Exon 9 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1149G>C	p.Leu383Phe	missense_variant	Exon 9 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1	c.444G>C	p.Leu148Phe	missense_variant	Exon 3 of 4			ENSP00000498779.1
WRN	ENST00000650667.1	n.*763G>C		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*763G>C		3_prime_UTR_variant	Exon 8 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Werner syndrome Uncertain:1

Dec 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 383 of the WRN protein (p.Leu383Phe). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.92
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.073
Sift	Benign	0.31	T
Sift4G	Benign	0.71	T
Polyphen		0.032	B
Vest4		0.025
MutPred		0.21		Gain of methylation at K384 (P = 0.0285);
MVP		0.49
MPC		0.075
ClinPred		0.072	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.046

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-30938692;