rs770716081

Variant names:

• chr13-36867271-A-T
• rs770716081
• NM_001127217.3:c.781+2T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PVS1_Moderate PP5 BS1_Supporting BS2_Supporting

The NM_001127217.3(SMAD9):​c.781+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,524,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: SMAD9 NM_001127217.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.53
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07905983 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 13-36867271-A-T is Pathogenic according to our data. Variant chr13-36867271-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541761.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000191 (262/1372616) while in subpopulation NFE AF = 0.00024 (253/1054602). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAdExome4. There are 127 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 13 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.781+2T>A		splice_donor_variant, intron_variant	Intron 4 of 6	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.781+2T>A		splice_donor_variant, intron_variant	Intron 4 of 6	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.671-1513T>A		intron_variant	Intron 3 of 5	1		ENSP00000239885.6
SMAD9	ENST00000399275.7	n.*381-1513T>A		intron_variant	Intron 3 of 5	1		ENSP00000382216.3
SMAD9	ENST00000715264.1	c.781+2T>A		splice_donor_variant, intron_variant	Intron 4 of 6			ENSP00000520435.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000767 AC: 12 AN: 156480 AF XY: 0.000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000191 AC: 262 AN: 1372616 Hom.: 0 Cov.: 25 AF XY: 0.000187 AC XY: 127 AN XY: 678618

African (AFR) AF: 0.00 AC: 0 AN: 31058

American (AMR) AF: 0.0000561 AC: 2 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35602

South Asian (SAS) AF: 0.00 AC: 0 AN: 78664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.000240 AC: 253 AN: 1054602

Other (OTH) AF: 0.000123 AC: 7 AN: 57084

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74298

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000814 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pulmonary hypertension, primary, 2 Pathogenic:2

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the SMAD9 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMAD9 are known to be pathogenic (PMID: 19419974, 31727138). This variant is present in population databases (rs770716081, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SMAD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 541761). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Identified in a patient with hypoplastic left heart syndrome, however, this patient also harbors variants in other genes (PMID: 28530678); This variant is associated with the following publications: (PMID: 28530678) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		3.5
GERP RS		4.2
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.010		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: rs770716081; hg19: chr13-37441408;