rs576434

Variant names:

• chr13-36884002-T-C
• rs576434
• NM_001127217.3:c.-186-4127A>G

Variant summary

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

The NM_001127217.3(SMAD9):​c.-186-4127A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 151,898 control chromosomes in the GnomAD database, including 14,327 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 0.43 (14327 hom., cov: 31)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.600
• 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: 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.-186-4127A>G		intron_variant	Intron 1 of 6	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.-186-4127A>G		intron_variant	Intron 1 of 6	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.-186-4127A>G		intron_variant	Intron 1 of 5	1		ENSP00000239885.6
SMAD9	ENST00000715264.1	c.-186-4127A>G		intron_variant	Intron 1 of 6			ENSP00000520435.1
SMAD9	ENST00000483941.2	n.254-4127A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65657 AN: 151780 Hom.: 14307 Cov.: 31

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.433 AC: 65725 AN: 151898 Hom.: 14327 Cov.: 31 AF XY: 0.429 AC XY: 31834 AN XY: 74232

African (AFR) AF: 0.446 AC: 18458 AN: 41386

American (AMR) AF: 0.413 AC: 6295 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1589 AN: 3466

East Asian (EAS) AF: 0.417 AC: 2147 AN: 5150

South Asian (SAS) AF: 0.394 AC: 1900 AN: 4822

European-Finnish (FIN) AF: 0.385 AC: 4072 AN: 10564

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30032 AN: 67936

Other (OTH) AF: 0.446 AC: 941 AN: 2110

Alfa AF: 0.437 Hom.: 8123

Bravo AF: 0.438

Asia WGS AF: 0.462 AC: 1607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		0.60
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: rs576434; hg19: chr13-37458139;