rs13438802

chr8-31090838-T-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.1725T>C(p.Tyr575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,606,684 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.07

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=-0.53).
• BP6: Variant 8-31090838-T-C is Benign according to our data. Variant chr8-31090838-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 238129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00473 (720/152134) while in subpopulation AFR AF= 0.0169 (703/41552). AF 95% confidence interval is 0.0159. There are 4 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.1725T>C	p.Tyr575=	synonymous_variant	15/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.1725T>C	p.Tyr575=	synonymous_variant	15/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.358T>C		non_coding_transcript_exon_variant	3/23	1
WRN	ENST00000650667.1	c.*1339T>C		3_prime_UTR_variant, NMD_transcript_variant	14/34

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 721 AN: 152016 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 250598 Hom.: 2 AF XY: 0.000805 AC XY: 109 AN XY: 135476

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000448 AC: 652 AN: 1454550 Hom.: 5 Cov.: 30 AF XY: 0.000384 AC XY: 278 AN XY: 723360

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.000715

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152134 Hom.: 4 Cov.: 32 AF XY: 0.00465 AC XY: 346 AN XY: 74406

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00552

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:3

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 19, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2021

- -

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	-0.53
Cadd	Benign	6.2
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs13438802; hg19: chr8-30948354;