Genetic Variant SMG1:p.Ser854Asn (chr16-18869926-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015092.5(SMG1):c.2561G>A(p.Ser854Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,530,566 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SMG1
NM_015092.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Publications

0 publications found

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:

LOC124903799 (HGNC:):

LOC124903799 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20452675).

BS2

High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015092.5. 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
	SMG1	NM_015092.5	MANE Select	c.2561G>A	p.Ser854Asn	missense	Exon 19 of 63	NP_055907.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMG1	ENST00000446231.7	TSL:1 MANE Select	c.2561G>A	p.Ser854Asn	missense	Exon 19 of 63	ENSP00000402515.3	Q96Q15-1
SMG1	ENST00000565324.5	TSL:1	c.2231G>A	p.Ser744Asn	missense	Exon 17 of 61	ENSP00000456259.1	J3KRA9
SMG1	ENST00000940395.1		c.2561G>A	p.Ser854Asn	missense	Exon 19 of 63	ENSP00000610454.1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000103

AC:

AN:

203668

AF XY:

0.000109

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000189

GnomAD4 exome

AF:

0.000162

AC:

223

AN:

1378462

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

114

AN XY:

688924

show subpopulations

African (AFR)

AF:

0.0000314

AC:

AN:

31880

American (AMR)

AF:

0.0000463

AC:

AN:

43190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25506

East Asian (EAS)

AF:

0.00

AC:

AN:

39210

South Asian (SAS)

AF:

0.00

AC:

AN:

82986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.000206

AC:

217

AN:

1054902

Other (OTH)

AF:

0.0000518

AC:

AN:

57944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000678

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0099

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

7.7

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.11

REVEL

Benign

0.17

Sift

Benign

0.53

Polyphen

0.98

Vest4

0.68

MutPred

0.18

Loss of disorder (P = 0.0964)

MVP

0.53

MPC

0.53

ClinPred

0.22

GERP RS

5.7

Varity_R

0.16

gMVP

0.32

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over