rs770716081

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PVS1_ModeratePP5_Very_StrongBS1_SupportingBS2_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 Likely pathogenic (★★).

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

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.53

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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 [Likely_pathogenic]. Clinvar id is 541761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 127 alleles in male gnomad4_exome subpopulation. Median coverage is 25. This position pass quality control queck. 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 link	c.781+2T>A		splice_donor_variant, intron_variant	Intron 4 of 6	ENST00000379826.5	NP_001120689.1	O15198-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD9	ENST00000379826.5 link	c.781+2T>A	splice_donor_variant, intron_variant	Intron 4 of 6	5	NM_001127217.3	ENSP00000369154.4	O15198-1
SMAD9	ENST00000350148.10 link	c.671-1513T>A	intron_variant	Intron 3 of 5	1		ENSP00000239885.6	O15198-2
SMAD9	ENST00000399275.7 link	n.*381-1513T>A	intron_variant	Intron 3 of 5	1		ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000767

AC:

AN:

156480

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

82946

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000187

AC XY:

127

AN XY:

678618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000561

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000240

Gnomad4 OTH exome

AF:

0.000123

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000814

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 2

Pathogenic:2

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Benign

0.96

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.85

GERP RS

4.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over