rs78249575

Positions:

chr13-36865752-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127217.3(SMAD9):c.788G>A(p.Arg263Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,560 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

SMAD9
NM_001127217.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.37

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019698441).

BP6

Variant 13-36865752-C-T is Benign according to our data. Variant chr13-36865752-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213812.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (209/152196) while in subpopulation NFE AF= 0.0024 (163/68016). AF 95% confidence interval is 0.0021. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD9	NM_001127217.3 linkuse as main transcript	c.788G>A	p.Arg263Gln	missense_variant	5/7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5 linkuse as main transcript	c.788G>A	p.Arg263Gln	missense_variant	5/7	5	NM_001127217.3	ENSP00000369154	P1	O15198-1
SMAD9	ENST00000350148.10 linkuse as main transcript	c.677G>A	p.Arg226Gln	missense_variant	4/6	1		ENSP00000239885		O15198-2
SMAD9	ENST00000399275.7 linkuse as main transcript	c.*387G>A		3_prime_UTR_variant, NMD_transcript_variant	4/6	1		ENSP00000382216

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00113

AC:

284

AN:

250808

Hom.:

AF XY:

0.00109

AC XY:

148

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00168

AC:

2452

AN:

1461364

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1203

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00204

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152196

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00113

AC:

137

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2015

p.Arg263Gln (CGA>CAA): c.788 G>A in exon 5 in the SMAD9 gene (NM_001127217.2). The R263Q variant in the SMAD9 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. This variant is a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a residue that is conserved across most mammalian species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The R263Q variant was observed at a frequency of 0.1%, 10/8600 alleles, in individuals of European ancestry by the NHLBI Exome Sequencing Project. We interpret R263Q as a variant of unknown significance. This variant was found in SMAD9. -

SMAD9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.20

DEOGEN2

Benign

0.23

T;.;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

.;T;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.49

N;.;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.3

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.36

MVP

0.93

MPC

0.26

ClinPred

0.020

GERP RS

3.5

Varity_R

0.097

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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