Genetic Variant SMG1:p.Ala3325Ala (chr16-18817390-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_015092.5(SMG1):c.9975G>A(p.Ala3325Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,608,566 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

SMG1
NM_015092.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.19

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 16-18817390-C-T is Benign according to our data. Variant chr16-18817390-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2646268.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.19 with no splicing effect.

BS2

High AC in GnomAd4 at 117 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.9975G>A	p.Ala3325Ala	synonymous	Exon 57 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.9975G>A	p.Ala3325Ala	synonymous	Exon 57 of 63	ENSP00000402515.3	Q96Q15-1
SMG1	ENST00000565324.5	TSL:1	c.9645G>A	p.Ala3215Ala	synonymous	Exon 55 of 61	ENSP00000456259.1	J3KRA9
SMG1	ENST00000940395.1		c.9975G>A	p.Ala3325Ala	synonymous	Exon 57 of 63	ENSP00000610454.1

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

116

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00113

AC:

270

AN:

239304

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00163

Gnomad EAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.00128

AC:

1867

AN:

1456362

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

964

AN XY:

723814

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33422

American (AMR)

AF:

0.000774

AC:

AN:

43936

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

25958

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39596

South Asian (SAS)

AF:

0.00203

AC:

173

AN:

85182

European-Finnish (FIN)

AF:

0.0000753

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00137

AC:

1515

AN:

1109162

Other (OTH)

AF:

0.00154

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000769

AC:

117

AN:

152204

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41520

American (AMR)

AF:

0.000524

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00126

Hom.:

Bravo

AF:

0.000876

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.1

(source)

DANN

Benign

0.60

PhyloP100

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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