rs4987238

chr8-31081176-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000553.6(WRN):c.1149G>T(p.Leu383Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,040 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. 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: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (20 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O: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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043698847).
• BP6: Variant 8-31081176-G-T is Benign according to our data. Variant chr8-31081176-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135452.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=2, Benign=2}. Variant chr8-31081176-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0015 (229/152298) while in subpopulation NFE AF= 0.00182 (124/68010). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.1149G>T	p.Leu383Phe	missense_variant	9/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.1149G>T	p.Leu383Phe	missense_variant	9/35	1	NM_000553.6	P1
WRN	ENST00000651642.1	c.444G>T	p.Leu148Phe	missense_variant	3/4
WRN	ENST00000650667.1	c.*763G>T		3_prime_UTR_variant, NMD_transcript_variant	8/34

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00212 AC: 530 AN: 250474 Hom.: 10 AF XY: 0.00232 AC XY: 314 AN XY: 135388

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00210 AC: 3064 AN: 1461742 Hom.: 20 Cov.: 32 AF XY: 0.00219 AC XY: 1595 AN XY: 727168

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00310 Hom.: 16

Bravo AF: 0.00175

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	This variant is associated with the following publications: (PMID: 28051113, 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WRN: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Werner syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	5.5
Dann	Benign	0.94
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.072
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		0.0050	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

LitVar

Other links and lift over

dbSNP: rs4987238; hg19: chr8-30938692; COSMIC: COSV105141082;