Genetic Variant SMG6:p.Asn1281Ser (chr17-2065673-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017575.5(SMG6):c.3842A>G(p.Asn1281Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000182 in 1,612,248 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 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

SMG6
NM_017575.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.14

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021748126).

BS2

High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017575.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMG6	NM_017575.5	MANE Select	c.3842A>G	p.Asn1281Ser	missense	Exon 17 of 19	NP_060045.4
SMG6	NM_001256827.2		c.1118A>G	p.Asn373Ser	missense	Exon 10 of 12	NP_001243756.1	Q86US8-3
SMG6	NM_001256828.1		c.1118A>G	p.Asn373Ser	missense	Exon 9 of 11	NP_001243757.1	Q86US8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMG6	ENST00000263073.11	TSL:1 MANE Select	c.3842A>G	p.Asn1281Ser	missense	Exon 17 of 19	ENSP00000263073.5	Q86US8-1
SMG6	ENST00000354901.8	TSL:1	c.1118A>G	p.Asn373Ser	missense	Exon 10 of 12	ENSP00000346977.4	Q86US8-3
SMG6	ENST00000573166.5	TSL:1	n.2172A>G		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000321

AC:

AN:

249050

AF XY:

0.000274

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0000498

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000169

AC:

247

AN:

1459926

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726326

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33472

American (AMR)

AF:

0.000380

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00287

AC:

AN:

26134

East Asian (EAS)

AF:

0.000428

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000579

AC:

AN:

51834

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000756

AC:

AN:

1111748

Other (OTH)

AF:

0.000580

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000302

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41572

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000590

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

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

-0.53

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

-0.12

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0057

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

4.1

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

REVEL

Benign

0.067

Sift

Benign

0.23

Sift4G

Benign

0.12

Polyphen

0.046

Vest4

0.29

MVP

0.46

MPC

0.13

ClinPred

0.024

GERP RS

4.5

Varity_R

0.23

gMVP

0.25

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over