rs200370409

Positions:

• chr8-31141563-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_000553.6(WRN):​c.3101A>T​(p.Tyr1034Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1034H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -5.65

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014153808).
• BP6: Variant 8-31141563-A-T is Benign according to our data. Variant chr8-31141563-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238146.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000223 (326/1461876) while in subpopulation MID AF= 0.00347 (20/5768). AF 95% confidence interval is 0.0023. There are 0 homozygotes in gnomad4_exome. There are 217 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.3101A>T	p.Tyr1034Phe	missense_variant	25/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.3101A>T	p.Tyr1034Phe	missense_variant	25/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.1734A>T		non_coding_transcript_exon_variant	13/23	1
WRN	ENST00000650667.1	c.*2715A>T		3_prime_UTR_variant, NMD_transcript_variant	24/34

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251480 Hom.: 0 AF XY: 0.000441 AC XY: 60 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.000298 AC XY: 217 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

WRN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The WRN c.3101A>T variant is predicted to result in the amino acid substitution p.Tyr1034Phe. This variant was reported in an individual with dyskeratosis/aplastic anemia (Patient #48, Arias-Salgado et al. 2019. PubMed ID: 30995915). This variant was also documented in an individual with multiple types of cancer (Hodgkin lymphoma, lymphangioma, breast carcinoma); however, this individual also harbored chain-terminating variants in CDKN2A and PMS1 (http://www.oncm.org/v02p0088.htm). This variant is reported in 0.12% of alleles in individuals of South Asian descent in gnomAD and is interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/238146/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Werner syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Wiskott-Aldrich syndrome Benign:1

Likely 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.0030
DANN	Benign	0.25
DEOGEN2	Benign	0.10	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.081
Sift	Benign	0.70	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.21
MVP		0.35
MPC		0.070
ClinPred		0.016	T
GERP RS		-12
Varity_R		0.22
gMVP		0.13

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: rs200370409; hg19: chr8-30999079; COSMIC: COSV53302433;