Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_001127217.3(SMAD9):c.65T>C(p.Leu22Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

SMAD9
NM_001127217.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 9.26

Publications

13 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 -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.15727222).

BP6

Variant 13-36879625-A-G is Benign according to our data. Variant chr13-36879625-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213811.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (178/152268) while in subpopulation NFE AF = 0.00181 (123/68014). AF 95% confidence interval is 0.00155. There are 1 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 178 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.65T>C	p.Leu22Pro	missense	Exon 2 of 7	NP_001120689.1
SMAD9	NM_001378621.1		c.65T>C	p.Leu22Pro	missense	Exon 2 of 6	NP_001365550.1
SMAD9	NM_005905.6		c.65T>C	p.Leu22Pro	missense	Exon 2 of 6	NP_005896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.65T>C	p.Leu22Pro	missense	Exon 2 of 7	ENSP00000369154.4
SMAD9	ENST00000350148.10	TSL:1	c.65T>C	p.Leu22Pro	missense	Exon 2 of 6	ENSP00000239885.6
SMAD9	ENST00000399275.7	TSL:1	n.65T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000382216.3

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00134

AC:

337

AN:

251474

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00226

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00156

AC:

2277

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1102

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00316

AC:

169

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00181

AC:

2016

AN:

1112004

Other (OTH)

AF:

0.00119

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

155

310

466

621

776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00117

AC:

178

AN:

152268

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41558

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68014

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00161

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00138

AC:

168

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Pulmonary hypertension, primary, 2 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.7

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.99

MVP

0.93

MPC

0.55

ClinPred

0.11

GERP RS

5.5

Varity_R

0.98

gMVP

0.88

Mutation Taster

=87/13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs111748421

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over