NM_000553.6:c.1161G>A

Variant names:

• chr8-31081188-G-A
• rs1800391
• NM_000553.6:c.1161G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.1161G>A​(p.Met387Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,613,922 control chromosomes in the GnomAD database, including 5,480 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M387V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (425 hom., cov: 32)
  • Exomes 𝑓: 0.078 (5055 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.111
• Publications: 37 publications found

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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015295148).
• BP6: Variant 8-31081188-G-A is Benign according to our data. Variant chr8-31081188-G-A is described in ClinVar as Benign. ClinVar VariationId is 130757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.1161G>A	p.Met387Ile	missense	Exon 9 of 35	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.1161G>A	p.Met387Ile	missense	Exon 9 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.1161G>A	p.Met387Ile	missense	Exon 9 of 35	ENSP00000636235.1
	WRN	ENST00000860283.1		c.1161G>A	p.Met387Ile	missense	Exon 9 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9462 AN: 152120 Hom.: 424 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0741

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0660

GnomAD2 exomes AF: 0.0752 AC: 18831 AN: 250442 AF XY: 0.0800

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0607

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0821

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0778 AC: 113722 AN: 1461684 Hom.: 5055 Cov.: 32 AF XY: 0.0802 AC XY: 58332 AN XY: 727136

African (AFR) AF: 0.0110 AC: 368 AN: 33468

American (AMR) AF: 0.0619 AC: 2766 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3006 AN: 26128

East Asian (EAS) AF: 0.000857 AC: 34 AN: 39654

South Asian (SAS) AF: 0.125 AC: 10807 AN: 86236

European-Finnish (FIN) AF: 0.0814 AC: 4348 AN: 53410

Middle Eastern (MID) AF: 0.144 AC: 833 AN: 5766

European-Non Finnish (NFE) AF: 0.0782 AC: 86980 AN: 1111920

Other (OTH) AF: 0.0758 AC: 4580 AN: 60384

GnomAD4 genome AF: 0.0621 AC: 9460 AN: 152238 Hom.: 425 Cov.: 32 AF XY: 0.0642 AC XY: 4780 AN XY: 74430

African (AFR) AF: 0.0135 AC: 562 AN: 41558

American (AMR) AF: 0.0740 AC: 1132 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.114 AC: 550 AN: 4816

European-Finnish (FIN) AF: 0.0855 AC: 906 AN: 10592

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0817 AC: 5554 AN: 68006

Other (OTH) AF: 0.0649 AC: 137 AN: 2112

Alfa AF: 0.0760 Hom.: 1589

Bravo AF: 0.0558

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0716 AC: 276

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.0792 AC: 681

ExAC AF: 0.0751 AC: 9114

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Werner syndrome (5)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.1
DANN	Benign	0.53
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.11
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.076
Sift	Benign	0.34	T
Sift4G	Benign	0.26	T
Polyphen		0.20	B
Vest4		0.022
MutPred		0.24		Loss of disorder (P = 0.0513)
MPC		0.078
ClinPred		0.000023	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.091
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800391; hg19: chr8-30938704; COSMIC: COSV53296756;