13-36867298-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001127217.3(SMAD9):c.756T>C(p.His252His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,550,138 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 21 hom. )

Consequence

SMAD9
NM_001127217.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.498

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 13-36867298-A-G is Benign according to our data. Variant chr13-36867298-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.498 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00361 (550/152284) while in subpopulation AMR AF= 0.00785 (120/15294). AF 95% confidence interval is 0.00671. There are 1 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3 link	c.756T>C	p.His252His	synonymous_variant	Exon 4 of 7	ENST00000379826.5	NP_001120689.1	O15198-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD9	ENST00000379826.5 link	c.756T>C	p.His252His	synonymous_variant	Exon 4 of 7	5	NM_001127217.3	ENSP00000369154.4	O15198-1
SMAD9	ENST00000350148.10 link	c.671-1540T>C		intron_variant	Intron 3 of 5	1		ENSP00000239885.6	O15198-2
SMAD9	ENST00000399275.7 link	n.*381-1540T>C		intron_variant	Intron 3 of 5	1		ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

550

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00506

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00364

AC:

569

AN:

156490

Hom.:

AF XY:

0.00333

AC XY:

276

AN XY:

82946

show subpopulations

Gnomad AFR exome

AF:

0.000379

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00753

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.000475

Gnomad NFE exome

AF:

0.00562

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00437

AC:

6113

AN:

1397854

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

2977

AN XY:

689490

show subpopulations

Gnomad4 AFR exome

AF:

0.000729

Gnomad4 AMR exome

AF:

0.00431

Gnomad4 ASJ exome

AF:

0.00807

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000720

Gnomad4 FIN exome

AF:

0.000325

Gnomad4 NFE exome

AF:

0.00498

Gnomad4 OTH exome

AF:

0.00455

GnomAD4 genome

AF:

0.00361

AC:

550

AN:

152284

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00785

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00506

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00472

Hom.:

Bravo

AF:

0.00403

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMAD9: BP4, BP7, BS2 -

Pulmonary hypertension, primary, 2

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Dec 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His252His in exon 4 of SMAD9: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.6% (49/8748) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs146836873). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.8

DANN

Benign

0.38

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

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