Variant 17-59210059-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_018149.7(SMG8):c.8G>C(p.Gly3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,559,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SMG8
NM_018149.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15379512).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000122 (172/1407210) while in subpopulation MID AF= 0.000915 (5/5464). AF 95% confidence interval is 0.00036. There are 0 homozygotes in gnomad4_exome. There are 83 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG8	NM_018149.7 link	c.8G>C	p.Gly3Ala	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.8G>C	p.Gly3Ala	missense_variant	1/4	1	NM_018149.7	ENSP00000300917.4		Q8ND04-1
ENSG00000265303	ENST00000577660.1 link	c.136-4746G>C		intron_variant		3		ENSP00000464167.1		J3QRE1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000747

AC:

AN:

200702

Hom.:

AF XY:

0.0000836

AC XY:

AN XY:

107690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000349

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000944

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

172

AN:

1407210

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

696562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000361

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000578

AC:

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

Aug 12, 2021

The c.8G>C (p.G3A) alteration is located in exon 1 (coding exon 1) of the SMG8 gene. This alteration results from a G to C substitution at nucleotide position 8, causing the glycine (G) at amino acid position 3 to be replaced by an alanine (A). 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

Benign

0.10

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

T;.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.77

.;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.24

N;.;N

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.29

MVP

0.57

MPC

0.92

ClinPred

0.26

GERP RS

5.2

Varity_R

0.43

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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