Genetic Variant SMG1:p.Arg3543Gln (chr16-18812121-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015092.5(SMG1):c.10628G>A(p.Arg3543Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000478 in 1,610,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

SMG1
NM_015092.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

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:

ENSG00000260017 (HGNC:):

ENSG00000260017 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11309451).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG1	NM_015092.5 link	c.10628G>A	p.Arg3543Gln	missense_variant	Exon 61 of 63	ENST00000446231.7	NP_055907.3	Q96Q15-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMG1	ENST00000446231.7 link	c.10628G>A	p.Arg3543Gln	missense_variant	Exon 61 of 63	1	NM_015092.5	ENSP00000402515.3	Q96Q15-1
SMG1	ENST00000565324.5 link	c.10298G>A	p.Arg3433Gln	missense_variant	Exon 59 of 61	1		ENSP00000456259.1	J3KRA9
SMG1	ENST00000561940.1 link	n.854G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
ENSG00000260017	ENST00000569096.1 link	n.301C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000651

AC:

AN:

245744

Hom.:

AF XY:

0.0000675

AC XY:

AN XY:

133300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000334

Gnomad FIN exome

AF:

0.000469

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000480

AC:

AN:

1458886

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

725650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000675

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.000544

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000759

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10628G>A (p.R3543Q) alteration is located in exon 61 (coding exon 61) of the SMG1 gene. This alteration results from a G to A substitution at nucleotide position 10628, causing the arginine (R) at amino acid position 3543 to be replaced by a glutamine (Q). 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

-0.28

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.17

Sift

Benign

0.041

D;.

Polyphen

0.92

P;.

Vest4

0.70

MutPred

0.26

Loss of helix (P = 0.0068);.;

MVP

0.25

MPC

0.59

ClinPred

0.088

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.31

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