Genetic Variant SMG6:p.Ala198Ala (chr17-2300159-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_017575.5(SMG6):c.594T>C(p.Ala198Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,554 control chromosomes in the GnomAD database, including 305,590 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 24567 hom., cov: 31)

Exomes 𝑓: 0.62 ( 281023 hom. )

Consequence

SMG6
NM_017575.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.437

Publications

48 publications found

Variant links:

Genes affected

SMG6 (HGNC:17809): (SMG6 nonsense mediated mRNA decay factor) This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described. [provided by RefSeq, Feb 2014]

SMG6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP7

Synonymous conserved (PhyloP=-0.437 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG6	NM_017575.5 link	c.594T>C	p.Ala198Ala	synonymous_variant	Exon 2 of 19	ENST00000263073.11	NP_060045.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG6	ENST00000263073.11 link	c.594T>C	p.Ala198Ala	synonymous_variant	Exon 2 of 19	1	NM_017575.5	ENSP00000263073.5

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

84821

AN:

151598

Hom.:

24552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.622

Gnomad AMR

AF:

0.601

Gnomad ASJ

AF:

0.652

Gnomad EAS

AF:

0.695

Gnomad SAS

AF:

0.565

Gnomad FIN

AF:

0.644

Gnomad MID

AF:

0.548

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.572

GnomAD2 exomes

AF:

0.609

AC:

153027

AN:

251412

AF XY:

0.609

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.655

Gnomad ASJ exome

AF:

0.669

Gnomad EAS exome

AF:

0.682

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.615

Gnomad OTH exome

AF:

0.609

GnomAD4 exome

AF:

0.617

AC:

902565

AN:

1461834

Hom.:

281023

Cov.:

AF XY:

0.616

AC XY:

447729

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.381

AC:

12753

AN:

33478

American (AMR)

AF:

0.650

AC:

29079

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

17265

AN:

26136

East Asian (EAS)

AF:

0.725

AC:

28787

AN:

39700

South Asian (SAS)

AF:

0.570

AC:

49166

AN:

86258

European-Finnish (FIN)

AF:

0.638

AC:

34067

AN:

53364

Middle Eastern (MID)

AF:

0.552

AC:

3185

AN:

5768

European-Non Finnish (NFE)

AF:

0.622

AC:

691590

AN:

1112012

Other (OTH)

AF:

0.607

AC:

36673

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

25147

50294

75442

100589

125736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18530

37060

55590

74120

92650

<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:

0.559

AC:

84879

AN:

151720

Hom.:

24567

Cov.:

AF XY:

0.564

AC XY:

41798

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.403

AC:

16632

AN:

41314

American (AMR)

AF:

0.601

AC:

9163

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.652

AC:

2262

AN:

3470

East Asian (EAS)

AF:

0.695

AC:

3582

AN:

5154

South Asian (SAS)

AF:

0.567

AC:

2725

AN:

4810

European-Finnish (FIN)

AF:

0.644

AC:

6775

AN:

10528

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.616

AC:

41816

AN:

67890

Other (OTH)

AF:

0.571

AC:

1206

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1834

3668

5503

7337

9171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.593

Hom.:

48798

Bravo

AF:

0.551

Asia WGS

AF:

0.566

AC:

1967

AN:

3478

EpiCase

AF:

0.617

EpiControl

AF:

0.611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.54

(source)

DANN

Benign

0.56

PhyloP100

-0.44

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over