Variant chr19-43733363-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019108.4(SMG9):c.1300A>G(p.Met434Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMG9
NM_019108.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18155348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG9	NM_019108.4 link	c.1300A>G	p.Met434Val	missense_variant	12/14	ENST00000270066.11	NP_061981.2	Q9H0W8-1A0A024R0Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMG9	ENST00000270066.11 link	c.1300A>G	p.Met434Val	missense_variant	12/14	1	NM_019108.4	ENSP00000270066.6	Q9H0W8-1
SMG9	ENST00000601170.5 link	c.1300A>G	p.Met434Val	missense_variant	12/13	2		ENSP00000471398.1	Q9H0W8-2
SMG9	ENST00000594081.1 link	n.544A>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

The c.1300A>G (p.M434V) alteration is located in exon 12 (coding exon 11) of the SMG9 gene. This alteration results from a A to G substitution at nucleotide position 1300, causing the methionine (M) at amino acid position 434 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.0089

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.57

N;.

REVEL

Benign

0.14

Sift

Benign

0.16

T;.

Sift4G

Benign

0.13

T;T

Polyphen

0.0010

B;.

Vest4

0.37

MutPred

0.22

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.57

MPC

0.42

ClinPred

0.32

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over