rs111748421

Variant names:

• chr13-36879625-A-G
• rs111748421
• NM_001127217.3:c.65T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_001127217.3(SMAD9):​c.65T>C​(p.Leu22Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 9.26
• Publications: 13 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 -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.15727222).
• BP6: Variant 13-36879625-A-G is Benign according to our data. Variant chr13-36879625-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213811.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (178/152268) while in subpopulation NFE AF = 0.00181 (123/68014). AF 95% confidence interval is 0.00155. There are 1 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.65T>C	p.Leu22Pro	missense_variant	Exon 2 of 7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.65T>C	p.Leu22Pro	missense_variant	Exon 2 of 7	5	NM_001127217.3	ENSP00000369154.4

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152150 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00134 AC: 337 AN: 251474 AF XY: 0.00132

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00156 AC: 2277 AN: 1461884 Hom.: 4 Cov.: 32 AF XY: 0.00152 AC XY: 1102 AN XY: 727244

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00316 AC: 169 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00181 AC: 2016 AN: 1112004

Other (OTH) AF: 0.00119 AC: 72 AN: 60394

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152268 Hom.: 1 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74440

African (AFR) AF: 0.000265 AC: 11 AN: 41558

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68014

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00161 Hom.: 3

Bravo AF: 0.000778

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu22Pro (CTA>CCA): c.65 T>C in exon 2 of the SMAD9 gene (NM_001127217.2). A variant of unknown significance has been identified in the SMAD9 gene. To our knowledge, the L22P variant has not been published as a mutation nor as a benign polymorphism. The L22P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the NHLBI Exome Sequencing Project and the 1000 Genomes Project identified L22P in 0.1%-0.6% of alleles from individuals of European background (of note, L22P was detected in 3/168 or 1.8% of alleles in Utah Residents with Northern and Western European ancestry), indicating it may be a rare benign variant in this population. Additionally, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in PAH-ARRHYTHMIA -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pulmonary hypertension, primary, 2 Uncertain:1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMAD9 c.65T>C; p.Leu22Pro variant (rs111748421) is reported in the literature in individuals affected with unexplained high bone mass (Gregson 2019). This variant is reported in ClinVar (Variation ID: 213811), and is found in the general population with an overall allele frequency of 0.14% (387/282856 alleles, including 4 homozygotes) in the Genome Aggregation Database. The leucine at codon 22 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.878). Due to limited information, the clinical significance of the p.Leu22Pro variant is uncertain at this time. References: Gregson CL et al. A rare SMAD9 mutation identifies the BMP signaling pathway as a potential osteoanabolic target. J Bone Miner Res. 2020 Jan;35(1):92-105. PMID: 31525280 -

not specified Uncertain:1

Mar 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Leu22Pro vari ant in SMAD9 has not been previously reported in individuals with pulmonary hype rtension, but has been identified in 0.2% (152/66658) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s111748421). This variant has also been identified in ClinVar (Variant ID: 21381 1). Computational prediction tools and conservation analysis suggest that the p. Leu22Pro variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, while the clinical significanc e of the p.Leu22Pro variant is uncertain, its frequency suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.7	H;H;H
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MVP		0.93
MPC		0.55
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.98
gMVP		0.88
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs111748421; hg19: chr13-37453762; COSMIC: COSV104669798;