Genetic Variant SMAD9:p.Thr248Ile (chr13-36867311-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001127217.3(SMAD9):c.743C>T(p.Thr248Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000715 in 1,398,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T248K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

SMAD9
NM_001127217.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15600702).

BS2

High AC in GnomAdExome4 at 10 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.743C>T	p.Thr248Ile	missense_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.743C>T	p.Thr248Ile	missense_variant	Exon 4 of 7	5	NM_001127217.3	ENSP00000369154.4	O15198-1
SMAD9	ENST00000350148.10 link	c.671-1553C>T		intron_variant	Intron 3 of 5	1		ENSP00000239885.6	O15198-2
SMAD9	ENST00000399275.7 link	n.*381-1553C>T		intron_variant	Intron 3 of 5	1		ENSP00000382216.3	A0A7I2R5A4
SMAD9	ENST00000715264.1 link	c.743C>T	p.Thr248Ile	missense_variant	Exon 4 of 7			ENSP00000520435.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000715

AC:

AN:

1398850

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689958

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31580

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000834

AC:

AN:

1078512

Other (OTH)

AF:

0.00

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.39

.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.67

N;N

PhyloP100

2.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.27

Sift

Benign

0.15

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;B

Vest4

0.069

MutPred

0.37

Gain of catalytic residue at V253 (P = 0.0045);Gain of catalytic residue at V253 (P = 0.0045);

MVP

0.93

MPC

0.24

ClinPred

0.066

GERP RS

2.6

Varity_R

0.042

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over