chr13-36879486-G-T

Variant names:

• chr13-36879486-G-T
• rs146583835
• NM_001127217.3:c.204C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127217.3(SMAD9):​c.204C>A​(p.Cys68*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD9 NM_001127217.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.370
• Publications: 5 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-36879486-G-T is Pathogenic according to our data. Variant chr13-36879486-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 548690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.204C>A	p.Cys68*	stop_gained	Exon 2 of 7	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.204C>A	p.Cys68*	stop_gained	Exon 2 of 6	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.204C>A	p.Cys68*	stop_gained	Exon 2 of 6	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.204C>A	p.Cys68*	stop_gained	Exon 2 of 7	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.204C>A	p.Cys68*	stop_gained	Exon 2 of 6	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.204C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Pulmonary arterial hypertension associated with congenital heart disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.51	D
PhyloP100		-0.37
Vest4		0.82
GERP RS		-1.8
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs146583835; hg19: chr13-37453623;