13-36908022-A-G

Variant names:

• chr13-36908022-A-G
• rs9576135
• NM_001127217.3:c.-187+12094T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127217.3(SMAD9):​c.-187+12094T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,034 control chromosomes in the GnomAD database, including 19,896 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19896 hom., cov: 32)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	NM_001127217.3	MANE Select	c.-187+12094T>C		intron	N/A	NP_001120689.1
	SMAD9	NM_001378621.1		c.-187+11989T>C		intron	N/A	NP_001365550.1
	SMAD9	NM_005905.6		c.-187+12094T>C		intron	N/A	NP_005896.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.-187+12094T>C		intron	N/A	ENSP00000369154.4
	SMAD9	ENST00000350148.10	TSL:1	c.-187+12094T>C		intron	N/A	ENSP00000239885.6
	SMAD9	ENST00000715264.1		c.-187+12094T>C		intron	N/A	ENSP00000520435.1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76614 AN: 151918 Hom.: 19873 Cov.: 32

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.504 AC: 76670 AN: 152034 Hom.: 19896 Cov.: 32 AF XY: 0.503 AC XY: 37353 AN XY: 74312

African (AFR) AF: 0.620 AC: 25693 AN: 41468

American (AMR) AF: 0.453 AC: 6928 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1598 AN: 3462

East Asian (EAS) AF: 0.598 AC: 3078 AN: 5148

South Asian (SAS) AF: 0.464 AC: 2237 AN: 4826

European-Finnish (FIN) AF: 0.432 AC: 4560 AN: 10566

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31078 AN: 67956

Other (OTH) AF: 0.510 AC: 1075 AN: 2106

Alfa AF: 0.473 Hom.: 3501

Bravo AF: 0.514

Asia WGS AF: 0.576 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.0
DANN	Benign	0.84
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs9576135; hg19: chr13-37482159;