chr13-36848697-G-T

Position:

• chr13-36848697-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127217.3(SMAD9):​c.1383C>A​(p.Asn461Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

Genes affected

SMAD9 (HGNC:6774): (SMAD family member 9) The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41293713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.1383C>A	p.Asn461Lys	missense_variant	7/7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.1383C>A	p.Asn461Lys	missense_variant	7/7	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.1272C>A	p.Asn424Lys	missense_variant	6/6	1		ENSP00000239885.6
SMAD9	ENST00000399275.7	n.*982C>A		non_coding_transcript_exon_variant	6/6	1		ENSP00000382216.3
SMAD9	ENST00000399275.7	n.*982C>A		3_prime_UTR_variant	6/6	1		ENSP00000382216.3

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

Pulmonary hypertension, primary, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.59	D;.;D
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.6	D;N;D
REVEL	Uncertain	0.41
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.93	P;B;P
Vest4		0.58
MutPred		0.33		Gain of methylation at N461 (P = 0.003);.;Gain of methylation at N461 (P = 0.003);
MVP		0.98
MPC		0.58
ClinPred		0.82	D
GERP RS		3.7
Varity_R		0.39
gMVP		0.16

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: rs2058051255; hg19: chr13-37422834;