13-36867298-A-G

Position:

• chr13-36867298-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127217.3(SMAD9):​c.756T>C​(p.His252=) 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 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 criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.498

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 -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]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.756T>C	p.His252=	synonymous_variant	4/7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.756T>C	p.His252=	synonymous_variant	4/7	5	NM_001127217.3	ENSP00000369154	P1
SMAD9	ENST00000350148.10	c.671-1540T>C		intron_variant		1		ENSP00000239885
SMAD9	ENST00000399275.7	c.*381-1540T>C		intron_variant, NMD_transcript_variant		1		ENSP00000382216

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

GnomAD3 exomes AF: 0.00364 AC: 569 AN: 156490 Hom.: 3 AF XY: 0.00333 AC XY: 276 AN XY: 82946

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 SAS exome AF: 0.000527

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

Gnomad4 AFR exome AF: 0.000729

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.00807

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000720

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.00498

Gnomad4 OTH exome AF: 0.00455

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

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00506

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00472 Hom.: 2

Bravo AF: 0.00403

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Sep 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 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

Dec 09, 2015

p.His252His in exon 4 of SMAD9: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.6% (49/8748) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs146836873). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.8
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs146836873; hg19: chr13-37441435;