rs145080962

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000553.6(WRN):​c.1577-17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,601,474 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

WRN
NM_000553.6 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.75
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 8-31088873-T-G is Benign according to our data. Variant chr8-31088873-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 256706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (513/152204) while in subpopulation AFR AF= 0.0117 (488/41562). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WRNNM_000553.6 linkuse as main transcriptc.1577-17T>G intron_variant ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkuse as main transcriptc.1577-17T>G intron_variant 1 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000521620.5 linkuse as main transcriptn.278-17T>G intron_variant 1
WRNENST00000650667.1 linkuse as main transcriptn.*1191-17T>G intron_variant ENSP00000498593.1 A0A494C0M3

Frequencies

GnomAD3 genomes
AF:
0.00336
AC:
511
AN:
152086
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0117
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000917
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000988
AC:
235
AN:
237868
Hom.:
1
AF XY:
0.000679
AC XY:
87
AN XY:
128090
show subpopulations
Gnomad AFR exome
AF:
0.0126
Gnomad AMR exome
AF:
0.000922
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:
0.0000285
Gnomad OTH exome
AF:
0.000681
GnomAD4 exome
AF:
0.000373
AC:
540
AN:
1449270
Hom.:
3
Cov.:
30
AF XY:
0.000314
AC XY:
226
AN XY:
720056
show subpopulations
Gnomad4 AFR exome
AF:
0.0116
Gnomad4 AMR exome
AF:
0.00114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000591
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000299
Gnomad4 OTH exome
AF:
0.000987
GnomAD4 genome
AF:
0.00337
AC:
513
AN:
152204
Hom.:
2
Cov.:
32
AF XY:
0.00335
AC XY:
249
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0117
Gnomad4 AMR
AF:
0.000916
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00162
Hom.:
0
Bravo
AF:
0.00381
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Werner syndrome Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 29, 2019- -
Wiskott-Aldrich syndrome Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
23
DANN
Benign
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.51
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.51
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145080962; hg19: chr8-30946389; API