rs397514715

chr13-36879563-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_001127217.3(SMAD9):c.127A>G(p.Lys43Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a domain MH1 (size 124) in uniprot entity SMAD9_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001127217.3
• BS2: High AC in GnomAdExome at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.127A>G	p.Lys43Glu	missense_variant	2/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.127A>G	p.Lys43Glu	missense_variant	2/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.127A>G	p.Lys43Glu	missense_variant	2/6	1
SMAD9	ENST00000399275.7	c.127A>G	p.Lys43Glu	missense_variant, NMD_transcript_variant	1/6	1
SMAD9	ENST00000483941.2	n.566A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251490 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000614 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jun 07, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -

SMAD9-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2024

The SMAD9 c.127A>G variant is predicted to result in the amino acid substitution p.Lys43Glu. This variant has been reported in an individual with pulmonary arterial hypertension and functional studies were inconclusive as to the variant's effect on protein function (Nasim et al. 2011. PubMed ID: 21898662). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.9	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.93
MutPred		0.61		Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);
MVP		0.95
MPC		0.97
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514715; hg19: chr13-37453700; COSMIC: COSV100614679;