chr13-36879678-G-A

Variant names:

• chr13-36879678-G-A
• rs78237438
• NM_001127217.3:c.12C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1048 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	NM_001127217.3	MANE Select	c.12C>T	p.Thr4Thr	synonymous	Exon 2 of 7	NP_001120689.1
	SMAD9	NM_001378621.1		c.12C>T	p.Thr4Thr	synonymous	Exon 2 of 6	NP_001365550.1
	SMAD9	NM_005905.6		c.12C>T	p.Thr4Thr	synonymous	Exon 2 of 6	NP_005896.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.12C>T	p.Thr4Thr	synonymous	Exon 2 of 7	ENSP00000369154.4
	SMAD9	ENST00000350148.10	TSL:1	c.12C>T	p.Thr4Thr	synonymous	Exon 2 of 6	ENSP00000239885.6
	SMAD9	ENST00000399275.7	TSL:1	n.12C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000382216.3

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

GnomAD2 exomes AF: 0.00196 AC: 491 AN: 250662 AF XY: 0.00147

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 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

African (AFR) AF: 0.0236 AC: 790 AN: 33478

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5730

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1112012

Other (OTH) AF: 0.00176 AC: 106 AN: 60392

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

African (AFR) AF: 0.0231 AC: 962 AN: 41572

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00368 Hom.: 1

Bravo AF: 0.00793

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Pulmonary hypertension, primary, 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.7
DANN	Benign	0.72
PhyloP100		3.7
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs78237438; hg19: chr13-37453815;