chr19-43733712-C-T

Variant names:

• chr19-43733712-C-T
• rs201870805
• NM_019108.4:c.1124G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_019108.4(SMG9):​c.1124G>A​(p.Arg375His) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SMG9 NM_019108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26249063).

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.1124G>A	p.Arg375His	missense	Exon 11 of 14	NP_061981.2	Q9H0W8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG9	ENST00000270066.11	TSL:1 MANE Select	c.1124G>A	p.Arg375His	missense	Exon 11 of 14	ENSP00000270066.6	Q9H0W8-1
	SMG9	ENST00000892518.1		c.1217G>A	p.Arg406His	missense	Exon 11 of 14	ENSP00000562577.1
	SMG9	ENST00000892519.1		c.1190G>A	p.Arg397His	missense	Exon 11 of 14	ENSP00000562578.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000191

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251254 AF XY: 0.000110

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111994

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74434

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.77	N
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.073	T
Sift4G	Benign	0.11	T
Polyphen		0.83	P
Vest4		0.52
MVP		0.74
MPC		0.83
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.38
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs201870805; hg19: chr19-44237864;