13-36882104-G-T

Variant names:

• chr13-36882104-G-T
• rs648206
• NM_001127217.3:c.-186-2229C>A

Variant summary

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

The NM_001127217.3(SMAD9):​c.-186-2229C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,364 control chromosomes in the GnomAD database, including 26,709 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 0.58 (26709 hom., cov: 31)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.771
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	NM_001127217.3	MANE Select	c.-186-2229C>A		intron	N/A	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.-186-2229C>A		intron	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.-186-2229C>A		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.-186-2229C>A		intron	N/A	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.-186-2229C>A		intron	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000715264.1		c.-186-2229C>A		intron	N/A	ENSP00000520435.1	O15198-1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88417 AN: 151246 Hom.: 26670 Cov.: 31

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.568

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.574

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

GnomAD4 genome AF: 0.585 AC: 88511 AN: 151364 Hom.: 26709 Cov.: 31 AF XY: 0.583 AC XY: 43101 AN XY: 73932

African (AFR) AF: 0.733 AC: 30264 AN: 41262

American (AMR) AF: 0.527 AC: 8024 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1952 AN: 3452

East Asian (EAS) AF: 0.732 AC: 3733 AN: 5100

South Asian (SAS) AF: 0.538 AC: 2587 AN: 4810

European-Finnish (FIN) AF: 0.500 AC: 5221 AN: 10446

Middle Eastern (MID) AF: 0.572 AC: 166 AN: 290

European-Non Finnish (NFE) AF: 0.518 AC: 35112 AN: 67766

Other (OTH) AF: 0.579 AC: 1217 AN: 2102

Alfa AF: 0.545 Hom.: 84876

Bravo AF: 0.598

Asia WGS AF: 0.674 AC: 2341 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.7
DANN	Benign	0.44
PhyloP100		0.77
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: rs648206; hg19: chr13-37456241;