13-36848895-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127217.3(SMAD9):c.1261-76C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,482,780 control chromosomes in the GnomAD database, including 46,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6074 hom., cov: 32)
  • Exomes 𝑓: 0.24 (40277 hom.)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-36848895-G-A is Benign according to our data. Variant chr13-36848895-G-A is described in ClinVar as [Benign]. Clinvar id is 675286.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.1261-76C>T		intron_variant		ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.1261-76C>T		intron_variant		5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.1150-76C>T		intron_variant		1
SMAD9	ENST00000399275.7	c.*860-76C>T		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41834 AN: 151938 Hom.: 6064 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.243 AC: 323137 AN: 1330726 Hom.: 40277 AF XY: 0.244 AC XY: 163154 AN XY: 667904

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.337

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.275 AC: 41874 AN: 152054 Hom.: 6074 Cov.: 32 AF XY: 0.275 AC XY: 20466 AN XY: 74320

Gnomad4 AFR AF: 0.363

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.287

Alfa AF: 0.245 Hom.: 4574

Bravo AF: 0.277

Asia WGS AF: 0.315 AC: 1097 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.9
Dann	Benign	0.55

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: rs4943431; hg19: chr13-37423032; COSMIC: COSV63206286; COSMIC: COSV63206286;