Variant 17-59210064-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_018149.7(SMG8):c.13G>A(p.Val5Met) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,561,156 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

SMG8
NM_018149.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

Variant links:

Genes affected

SMG8 (HGNC:25551): (SMG8 nonsense mediated mRNA decay factor) Involved in nuclear-transcribed mRNA catabolic process, nonsense-mediated decay and regulation of protein kinase activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

SMG8 links:

ENSG00000265303 (HGNC:):

ENSG00000265303 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016122878).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000926 (141/152246) while in subpopulation NFE AF= 0.00159 (108/68016). AF 95% confidence interval is 0.00135. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG8	NM_018149.7 link	c.13G>A	p.Val5Met	missense_variant	1/4	ENST00000300917.10	NP_060619.4	Q8ND04-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG8	ENST00000300917.10 link	c.13G>A	p.Val5Met	missense_variant	1/4	1	NM_018149.7	ENSP00000300917.4		Q8ND04-1
ENSG00000265303	ENST00000577660.1 link	c.136-4741G>A		intron_variant		3		ENSP00000464167.1		J3QRE1

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000946

AC:

190

AN:

200926

Hom.:

AF XY:

0.000954

AC XY:

103

AN XY:

108000

show subpopulations

Gnomad AFR exome

AF:

0.000261

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000186

Gnomad FIN exome

AF:

0.0000624

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00110

AC:

1543

AN:

1408910

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

798

AN XY:

697692

show subpopulations

Gnomad4 AFR exome

AF:

0.000159

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000898

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000193

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.000688

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152246

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.000952

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000899

AC:

109

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.13G>A (p.V5M) alteration is located in exon 1 (coding exon 1) of the SMG8 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the valine (V) at amino acid position 5 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.83

.;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.060

N;.;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

0.94

P;.;P

Vest4

0.42

MVP

0.54

MPC

0.74

ClinPred

0.15

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.43

gMVP

0.53

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over