chr19-43733682-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019108.4(SMG9):c.1154G>A(p.Arg385Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,062 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 11 hom. )

Consequence

SMG9
NM_019108.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.58

Publications

3 publications found

Variant links:

Genes affected

SMG9 (HGNC:25763): (SMG9 nonsense mediated mRNA decay factor) This gene encodes a regulatory subunit of the SMG1 complex, which plays a critical role in nonsense-mediated mRNA decay (NMD). Binding of the encoded protein to the SMG1 complex kinase scaffold protein results in the inhibition of its kinase activity. Mutations in this gene cause a multiple congenital anomaly syndrome in human patients, characterized by brain malformation, congenital heart disease and other features. [provided by RefSeq, Jul 2016]

SMG9 Gene-Disease associations (from GenCC):

heart and brain malformation syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

SMG9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006526023).

BP6

Variant 19-43733682-C-T is Benign according to our data. Variant chr19-43733682-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 712249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00651 (991/152178) while in subpopulation AFR AF = 0.0222 (922/41486). AF 95% confidence interval is 0.021. There are 10 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019108.4. 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
	SMG9	NM_019108.4	MANE Select	c.1154G>A	p.Arg385Gln	missense	Exon 11 of 14	NP_061981.2	Q9H0W8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMG9	ENST00000270066.11	TSL:1 MANE Select	c.1154G>A	p.Arg385Gln	missense	Exon 11 of 14	ENSP00000270066.6	Q9H0W8-1
SMG9	ENST00000892518.1		c.1247G>A	p.Arg416Gln	missense	Exon 11 of 14	ENSP00000562577.1
SMG9	ENST00000892519.1		c.1220G>A	p.Arg407Gln	missense	Exon 11 of 14	ENSP00000562578.1

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

985

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00186

AC:

467

AN:

251428

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000781

AC:

1141

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000718

AC XY:

522

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0214

AC:

717

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00551

AC:

144

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000872

AC:

AN:

1112008

Other (OTH)

AF:

0.00174

AC:

105

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00651

AC:

991

AN:

152178

Hom.:

Cov.:

AF XY:

0.00652

AC XY:

485

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0222

AC:

922

AN:

41486

American (AMR)

AF:

0.00177

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00714

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Heart and brain malformation syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Benign

-0.21

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

1.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.39

REVEL

Benign

0.057

Sift

Benign

0.37

Sift4G

Benign

0.45

Polyphen

0.011

Vest4

0.29

MVP

0.59

MPC

0.49

ClinPred

0.020

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.24

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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