chr13-36867298-A-C

Variant names:

• chr13-36867298-A-C
• rs146836873
• NM_001127217.3:c.756T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. 14/24 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 Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• Publications: 1 publications found

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]

SMAD9 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127217.3. 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
	SMAD9	NM_001127217.3	MANE Select	c.756T>G	p.His252Gln	missense	Exon 4 of 7	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.671-1540T>G		intron	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.671-1540T>G		intron	N/A	NP_005896.1	O15198-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.756T>G	p.His252Gln	missense	Exon 4 of 7	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.671-1540T>G		intron	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.*381-1540T>G		intron	N/A	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.76	N
PhyloP100		-0.50
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.23
Sift	Benign	0.58	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.42		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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs146836873; hg19: chr13-37441435;