Genetic Variant SMAD9:p.His252His (chr13-36867298-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

1 publications found

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 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

SMAD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 550 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD9	NM_001127217.3	MANE Select	c.756T>C	p.His252His	synonymous	Exon 4 of 7	NP_001120689.1
SMAD9	NM_001378621.1		c.671-1540T>C		intron	N/A	NP_001365550.1
SMAD9	NM_005905.6		c.671-1540T>C		intron	N/A	NP_005896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.756T>C	p.His252His	synonymous	Exon 4 of 7	ENSP00000369154.4
SMAD9	ENST00000350148.10	TSL:1	c.671-1540T>C		intron	N/A	ENSP00000239885.6
SMAD9	ENST00000399275.7	TSL:1	n.*381-1540T>C		intron	N/A	ENSP00000382216.3

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

GnomAD2 exomes

AF:

0.00364

AC:

569

AN:

156490

AF XY:

0.00333

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 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

African (AFR)

AF:

0.000729

AC:

AN:

31566

American (AMR)

AF:

0.00431

AC:

154

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

203

AN:

25166

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35724

South Asian (SAS)

AF:

0.000720

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.000325

AC:

AN:

49274

Middle Eastern (MID)

AF:

0.00544

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00498

AC:

5364

AN:

1077580

Other (OTH)

AF:

0.00455

AC:

264

AN:

57962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

246

492

738

984

1230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00361

AC:

550

AN:

152284

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41558

American (AMR)

AF:

0.00785

AC:

120

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00506

AC:

344

AN:

68024

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.8

(source)

DANN

Benign

0.38

PhyloP100

-0.50

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over