rs146836873

chr13-36867298-A-Cchr13-36867298-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127217.3(SMAD9):c.756T>G(p.His252Gln) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H252H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08215505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.756T>G	p.His252Gln	missense_variant	4/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.756T>G	p.His252Gln	missense_variant	4/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.671-1540T>G		intron_variant		1
SMAD9	ENST00000399275.7	c.*381-1540T>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	14
Dann	Benign	0.33
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.76	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.23
Sift	Benign	0.58	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0	B;B
Vest4		0.090
MutPred		0.42		Gain of catalytic residue at V253 (P = 0.0059);Gain of catalytic residue at V253 (P = 0.0059);
MVP		0.79
MPC		0.23
ClinPred		0.050	T
GERP RS		-0.95
Varity_R		0.037
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs146836873; hg19: chr13-37441435;