8-31076195-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000553.6(WRN):c.747C>T(p.Asp249Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,534 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 3 hom. )

Consequence

WRN
NM_000553.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.607

Publications

1 publications found

Variant links:

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]

WRN Gene-Disease associations (from GenCC):

Werner syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
osteosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

WRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 8-31076195-C-T is Benign according to our data. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126. Variant chr8-31076195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 290126.

BP7

Synonymous conserved (PhyloP=-0.607 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000287 (42/1461534) while in subpopulation MID AF = 0.00607 (35/5764). AF 95% confidence interval is 0.00449. There are 3 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.747C>T	p.Asp249Asp	synonymous_variant	Exon 8 of 35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.747C>T	p.Asp249Asp	synonymous_variant	Exon 8 of 35	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000651642.1 link	c.42C>T	p.Asp14Asp	synonymous_variant	Exon 2 of 4			ENSP00000498779.1	A0A494C0Y6
WRN	ENST00000650667.1 link	n.*361C>T		non_coding_transcript_exon_variant	Exon 7 of 34			ENSP00000498593.1	A0A494C0M3
WRN	ENST00000650667.1 link	n.*361C>T		3_prime_UTR_variant	Exon 7 of 34			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111812

Other (OTH)

AF:

0.0000497

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 06, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Werner syndrome

Benign:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.0

(source)

DANN

Benign

0.27

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over