rs11574345

chr8-31142629-G-Achr8-31142629-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000553.6(WRN):c.3237G>A(p.Ser1079=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,592,336 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1079S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (9 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.513

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-31142629-G-A is Benign according to our data. Variant chr8-31142629-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.513 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000987 (150/152052) while in subpopulation EAS AF= 0.0239 (124/5186). AF 95% confidence interval is 0.0205. There are 2 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.3237G>A	p.Ser1079=	synonymous_variant	27/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.3237G>A	p.Ser1079=	synonymous_variant	27/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.1870G>A		non_coding_transcript_exon_variant	15/23	1
WRN	ENST00000650667.1	c.*2851G>A		3_prime_UTR_variant, NMD_transcript_variant	26/34

Frequencies

GnomAD3 genomes AF: 0.000994 AC: 151 AN: 151934 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00217 AC: 528 AN: 243824 Hom.: 6 AF XY: 0.00199 AC XY: 262 AN XY: 131932

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.0000912

Gnomad ASJ exome AF: 0.00216

Gnomad EAS exome AF: 0.0268

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00153

GnomAD4 exome AF: 0.000678 AC: 977 AN: 1440284 Hom.: 9 Cov.: 29 AF XY: 0.000628 AC XY: 449 AN XY: 715278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.0194

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000336

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000987 AC: 150 AN: 152052 Hom.: 2 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74318

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.00123

Asia WGS AF: 0.00810 AC: 28 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Wiskott-Aldrich syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.0
Dann	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11574345; hg19: chr8-31000145; COSMIC: COSV53302512;