13-36867311-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001127217.3(SMAD9):​c.743C>T​(p.Thr248Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000715 in 1,398,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0000071 (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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15600702).
• BS2: High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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>T	p.Thr248Ile	missense	Exon 4 of 7	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.671-1553C>T		intron	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.671-1553C>T		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>T	p.Thr248Ile	missense	Exon 4 of 7	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.671-1553C>T		intron	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.*381-1553C>T		intron	N/A	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1398850 Hom.: 0 Cov.: 29 AF XY: 0.00000725 AC XY: 5 AN XY: 689958

African (AFR) AF: 0.0000317 AC: 1 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: 0.00000834 AC: 9 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	0.096
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.66
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.67	N
PhyloP100		2.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.37		Gain of catalytic residue at V253 (P = 0.0045)
MVP		0.93
MPC		0.24
ClinPred		0.066	T
GERP RS		2.6
Varity_R		0.042
gMVP		0.23
Mutation Taster		=99/1	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;