NM_019108.4:c.1435T>C

Variant names:

• chr19-43732907-A-G
• rs112534097
• NM_019108.4:c.1435T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_019108.4(SMG9):​c.1435T>C​(p.Ser479Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMG9 NM_019108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG9	NM_019108.4	c.1435T>C	p.Ser479Pro	missense_variant	Exon 13 of 14	ENST00000270066.11	NP_061981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG9	ENST00000270066.11	c.1435T>C	p.Ser479Pro	missense_variant	Exon 13 of 14	1	NM_019108.4	ENSP00000270066.6
SMG9	ENST00000601170.5	c.1435T>C	p.Ser479Pro	missense_variant	Exon 13 of 13	2		ENSP00000471398.1
SMG9	ENST00000600097.1	n.204T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1435T>C (p.S479P) alteration is located in exon 13 (coding exon 12) of the SMG9 gene. This alteration results from a T to C substitution at nucleotide position 1435, causing the serine (S) at amino acid position 479 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0068	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.15
Sift	Benign	0.083	T;.
Sift4G	Uncertain	0.049	D;D
Polyphen		0.61	P;.
Vest4		0.66
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.49
MPC		0.99
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.71

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

Other links and lift over

dbSNP: rs112534097; hg19: chr19-44237059;