13-36867311-G-C

Variant names:

• chr13-36867311-G-C
• rs79733377
• NM_001127217.3:c.743C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127217.3(SMAD9):​c.743C>G​(p.Thr248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T248K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.178498).

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.743C>G	p.Thr248Arg	missense	Exon 4 of 7	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.671-1553C>G		intron	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.671-1553C>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.743C>G	p.Thr248Arg	missense	Exon 4 of 7	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.671-1553C>G		intron	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.*381-1553C>G		intron	N/A	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398850 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 689958

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078512

Other (OTH) AF: 0.00 AC: 0 AN: 57986

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.58
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.29
Sift	Benign	0.29	T
Sift4G	Benign	0.49	T
Polyphen		0.025	B
Vest4		0.19
MutPred		0.37		Gain of catalytic residue at V253 (P = 0.0096)
MVP		0.91
MPC		0.26
ClinPred		0.068	T
GERP RS		2.6
Varity_R		0.052
gMVP		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs79733377; hg19: chr13-37441448;