rs140674886

Variant names:

• chr19-43733428-T-A
• NM_019108.4:c.1235A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-43733428-T-A
• chr19-43733428-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019108.4(SMG9):​c.1235A>T​(p.Asn412Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMG9 NM_019108.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG9	NM_019108.4	c.1235A>T	p.Asn412Ile	missense_variant	Exon 12 of 14	ENST00000270066.11	NP_061981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG9	ENST00000270066.11	c.1235A>T	p.Asn412Ile	missense_variant	Exon 12 of 14	1	NM_019108.4	ENSP00000270066.6
SMG9	ENST00000601170.5	c.1235A>T	p.Asn412Ile	missense_variant	Exon 12 of 13	2		ENSP00000471398.1
SMG9	ENST00000594081.1	n.479A>T		non_coding_transcript_exon_variant	Exon 2 of 2	4
SMG9	ENST00000598860.1	n.570A>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.012	D;D
Polyphen		0.047	B;.
Vest4		0.85
MutPred		0.47		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.57
MPC		0.58
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44237580;