rs78249575

chr13-36865752-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.37

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]

ACMG classification

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=3, 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.788G>A	p.Arg263Gln	missense_variant	5/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.788G>A	p.Arg263Gln	missense_variant	5/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.677G>A	p.Arg226Gln	missense_variant	4/6	1
SMAD9	ENST00000399275.7	c.*387G>A		3_prime_UTR_variant, NMD_transcript_variant	4/6	1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152078 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00109 AC XY: 148 AN XY: 135600

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.: 4 Cov.: 32 AF XY: 0.00165 AC XY: 1203 AN XY: 726992

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.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74412

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.: 2

Bravo AF: 0.00122

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00113 AC: 137

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

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	Invitae	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 condition Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	20
Dann	Benign	0.20
DEOGEN2	Benign	0.23	T;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.49	N;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs78249575; hg19: chr13-37439889;