13-36865751-TC-CT

Variant names:

• chr13-36865751-TC-CT
• NM_001127217.3:c.788_789delGAinsAG
• SMAD9 p.Arg263Gln

Variant summary

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

The NM_001127217.3(SMAD9):​c.788_789delGAinsAG​(p.Arg263Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• 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: PanelApp Australia, Ambry Genetics, 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.

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.788_789delGAinsAG	p.Arg263Gln	missense	N/A	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.677_678delGAinsAG	p.Arg226Gln	missense	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.677_678delGAinsAG	p.Arg226Gln	missense	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.788_789delGAinsAG	p.Arg263Gln	missense	N/A	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.677_678delGAinsAG	p.Arg226Gln	missense	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.*387_*388delGAinsAG		non_coding_transcript_exon	Exon 4 of 6	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-37439888;