rs78237438

Positions:

• chr13-36879678-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001127217.3(SMAD9):​c.12C>T​(p.Thr4Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.00134 in 1,614,132 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: SMAD9 NM_001127217.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.73

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 13-36879678-G-A is Benign according to our data. Variant chr13-36879678-G-A is described in ClinVar as [Benign]. Clinvar id is 227076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00688 (1048/152318) while in subpopulation AFR AF= 0.0231 (962/41572). AF 95% confidence interval is 0.0219. There are 9 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1048 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.12C>T	p.Thr4Thr	synonymous_variant	2/7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.12C>T	p.Thr4Thr	synonymous_variant	2/7	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.12C>T	p.Thr4Thr	synonymous_variant	2/6	1		ENSP00000239885.6
SMAD9	ENST00000399275.7	n.12C>T		non_coding_transcript_exon_variant	1/6	1		ENSP00000382216.3
SMAD9	ENST00000483941.2	n.451C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152200 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00196 AC: 491 AN: 250662 Hom.: 3 AF XY: 0.00147 AC XY: 199 AN XY: 135528

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000759 AC: 1110 AN: 1461814 Hom.: 10 Cov.: 32 AF XY: 0.000670 AC XY: 487 AN XY: 727206

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00688 AC: 1048 AN: 152318 Hom.: 9 Cov.: 33 AF XY: 0.00655 AC XY: 488 AN XY: 74484

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00333 Hom.: 0

Bravo AF: 0.00793

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary hypertension, primary, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Thr4Thr in exon 2 of SMAD9: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 2.7% (120/4406) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs78237438). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.7
DANN	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs78237438; hg19: chr13-37453815;