rs9531986

Variant names:

• chr13-36858722-A-G
• rs9531986
• NM_001127217.3:c.1004-5047T>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.1004-5047T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 152,080 control chromosomes in the GnomAD database, including 11,194 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 0.37 (11194 hom., cov: 32)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.1004-5047T>C		intron_variant	Intron 5 of 6	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.1004-5047T>C		intron_variant	Intron 5 of 6	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.893-5047T>C		intron_variant	Intron 4 of 5	1		ENSP00000239885.6
SMAD9	ENST00000399275.7	n.*603-5047T>C		intron_variant	Intron 4 of 5	1		ENSP00000382216.3
SMAD9	ENST00000715264.1	c.1004-5047T>C		intron_variant	Intron 5 of 6			ENSP00000520435.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56235 AN: 151960 Hom.: 11193 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.370 AC: 56239 AN: 152080 Hom.: 11194 Cov.: 32 AF XY: 0.372 AC XY: 27633 AN XY: 74326

African (AFR) AF: 0.223 AC: 9264 AN: 41476

American (AMR) AF: 0.382 AC: 5846 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1389 AN: 3468

East Asian (EAS) AF: 0.348 AC: 1798 AN: 5172

South Asian (SAS) AF: 0.341 AC: 1645 AN: 4824

European-Finnish (FIN) AF: 0.527 AC: 5568 AN: 10564

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29505 AN: 67972

Other (OTH) AF: 0.362 AC: 764 AN: 2112

Alfa AF: 0.412 Hom.: 3147

Bravo AF: 0.354

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.88
PhyloP100		-0.30
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: rs9531986; hg19: chr13-37432859; COSMIC: COSV63206157;