NM_001127217.3:c.756T>C

Variant names:

• chr13-36867298-A-G
• rs146836873
• NM_001127217.3:c.756T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127217.3(SMAD9):​c.756T>C​(p.His252His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,550,138 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (21 hom.)
• Consequence: SMAD9 NM_001127217.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.498
• Publications: 1 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-36867298-A-G is Benign according to our data. Variant chr13-36867298-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.498 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00361 (550/152284) while in subpopulation AMR AF = 0.00785 (120/15294). AF 95% confidence interval is 0.00671. There are 1 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 550 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.756T>C	p.His252His	synonymous	Exon 4 of 7	NP_001120689.1	O15198-1
	SMAD9	NM_001378621.1		c.671-1540T>C		intron	N/A	NP_001365550.1	O15198-2
	SMAD9	NM_005905.6		c.671-1540T>C		intron	N/A	NP_005896.1	O15198-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD9	ENST00000379826.5	TSL:5 MANE Select	c.756T>C	p.His252His	synonymous	Exon 4 of 7	ENSP00000369154.4	O15198-1
	SMAD9	ENST00000350148.10	TSL:1	c.671-1540T>C		intron	N/A	ENSP00000239885.6	O15198-2
	SMAD9	ENST00000399275.7	TSL:1	n.*381-1540T>C		intron	N/A	ENSP00000382216.3	A0A7I2R5A4

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00364 AC: 569 AN: 156490 AF XY: 0.00333

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00753

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000475

Gnomad NFE exome AF: 0.00562

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00437 AC: 6113 AN: 1397854 Hom.: 21 Cov.: 29 AF XY: 0.00432 AC XY: 2977 AN XY: 689490

African (AFR) AF: 0.000729 AC: 23 AN: 31566

American (AMR) AF: 0.00431 AC: 154 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 203 AN: 25166

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35724

South Asian (SAS) AF: 0.000720 AC: 57 AN: 79192

European-Finnish (FIN) AF: 0.000325 AC: 16 AN: 49274

Middle Eastern (MID) AF: 0.00544 AC: 31 AN: 5694

European-Non Finnish (NFE) AF: 0.00498 AC: 5364 AN: 1077580

Other (OTH) AF: 0.00455 AC: 264 AN: 57962

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74458

African (AFR) AF: 0.000866 AC: 36 AN: 41558

American (AMR) AF: 0.00785 AC: 120 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 68024

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00472 Hom.: 2

Bravo AF: 0.00403

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Pulmonary hypertension, primary, 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.8
DANN	Benign	0.38
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs146836873; hg19: chr13-37441435;