Genetic Variant NM_001127217.3:c.*298A>G (chr13-36848378-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001127217.3(SMAD9):c.*298A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 391,636 control chromosomes in the GnomAD database, including 1,104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.065 ( 637 hom., cov: 32)

Exomes 𝑓: 0.042 ( 467 hom. )

Consequence

SMAD9
NM_001127217.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3 link	c.*298A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000379826.5	NP_001120689.1	O15198-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD9	ENST00000379826.5 link	c.*298A>G	3_prime_UTR_variant	Exon 7 of 7	5	NM_001127217.3	ENSP00000369154.4	O15198-1
SMAD9	ENST00000350148.10 link	c.*298A>G	3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000239885.6	O15198-2
SMAD9	ENST00000715264.1 link	c.*298A>G	3_prime_UTR_variant	Exon 7 of 7			ENSP00000520435.1
SMAD9	ENST00000399275.7 link	n.*1301A>G	downstream_gene_variant		1		ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes

AF:

0.0644

AC:

9799

AN:

152088

Hom.:

622

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0470

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0559

GnomAD4 exome

AF:

0.0416

AC:

9955

AN:

239430

Hom.:

467

Cov.:

AF XY:

0.0473

AC XY:

6006

AN XY:

126994

show subpopulations

African (AFR)

AF:

0.146

AC:

1091

AN:

7460

American (AMR)

AF:

0.0226

AC:

218

AN:

9630

Ashkenazi Jewish (ASJ)

AF:

0.0481

AC:

341

AN:

7096

East Asian (EAS)

AF:

0.109

AC:

1422

AN:

13026

South Asian (SAS)

AF:

0.113

AC:

3642

AN:

32232

European-Finnish (FIN)

AF:

0.0130

AC:

150

AN:

11526

Middle Eastern (MID)

AF:

0.0683

AC:

AN:

1010

European-Non Finnish (NFE)

AF:

0.0174

AC:

2500

AN:

144082

Other (OTH)

AF:

0.0390

AC:

522

AN:

13368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

436

872

1308

1744

2180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.0647

AC:

9853

AN:

152206

Hom.:

637

Cov.:

AF XY:

0.0665

AC XY:

4950

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.158

AC:

6548

AN:

41486

American (AMR)

AF:

0.0328

AC:

501

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

163

AN:

3470

East Asian (EAS)

AF:

0.103

AC:

534

AN:

5174

South Asian (SAS)

AF:

0.127

AC:

609

AN:

4814

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10620

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0179

AC:

1217

AN:

68028

Other (OTH)

AF:

0.0558

AC:

118

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

424

848

1272

1696

2120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0346

Hom.:

259

Bravo

AF:

0.0670

Asia WGS

AF:

0.120

AC:

415

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.7

(source)

DANN

Benign

0.57

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over