Variant 16-18836186-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000446231.7(SMG1):c.7804G>A(p.Ala2602Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000801 in 1,612,030 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 3 hom. )

Consequence

SMG1
ENST00000446231.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

SMG1 (HGNC:30045): (SMG1 nonsense mediated mRNA decay associated PI3K related kinase) This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternatively spliced transcript variants have been described, but their full-length nature has yet to be determined. [provided by RefSeq, Mar 2013]

SMG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011856645).

BS2

High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG1	NM_015092.5 linkuse as main transcript	c.7804G>A	p.Ala2602Thr	missense_variant	48/63	ENST00000446231.7	NP_055907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG1	ENST00000446231.7 linkuse as main transcript	c.7804G>A	p.Ala2602Thr	missense_variant	48/63	1	NM_015092.5	ENSP00000402515	P1	Q96Q15-1
SMG1	ENST00000565324.5 linkuse as main transcript	c.7474G>A	p.Ala2492Thr	missense_variant	46/61	1		ENSP00000456259

Frequencies

GnomAD3 genomes

AF:

0.000696

AC:

106

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000752

AC:

184

AN:

244772

Hom.:

AF XY:

0.000851

AC XY:

113

AN XY:

132838

show subpopulations

Gnomad AFR exome

AF:

0.0000666

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.00515

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000233

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.000949

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.000812

AC:

1185

AN:

1459696

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

582

AN XY:

725866

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000473

Gnomad4 ASJ exome

AF:

0.00469

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000862

Gnomad4 OTH exome

AF:

0.000779

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152334

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000654

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00107

AC:

ExAC

AF:

0.000678

AC:

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

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.7804G>A (p.A2602T) alteration is located in exon 48 (coding exon 48) of the SMG1 gene. This alteration results from a G to A substitution at nucleotide position 7804, causing the alanine (A) at amino acid position 2602 to be replaced by a threonine (T). 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

0.075

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

T;T

Eigen

Benign

0.050

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0071

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.20

N;.

MutationTaster

Benign

0.79

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.87

N;.

REVEL

Benign

0.10

Sift

Benign

0.31

T;.

Polyphen

0.44

B;.

Vest4

0.26

MVP

0.38

MPC

0.28

ClinPred

0.0093

GERP RS

4.9

Varity_R

0.078

gMVP

0.13

Splicing

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