13-36848580-CAT-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001127217.3(SMAD9):c.*94_*95del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,148,244 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: SMAD9 NM_001127217.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0014 (1399/995958) while in subpopulation NFE AF= 0.00178 (1224/688186). AF 95% confidence interval is 0.0017. There are 4 homozygotes in gnomad4_exome. There are 700 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.*94_*95del		3_prime_UTR_variant	7/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.*94_*95del		3_prime_UTR_variant	7/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.*94_*95del		3_prime_UTR_variant	6/6	1
SMAD9	ENST00000399275.7			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00140 AC: 1399 AN: 995958 Hom.: 4 AF XY: 0.00136 AC XY: 700 AN XY: 516384

Gnomad4 AFR exome AF: 0.00124

Gnomad4 AMR exome AF: 0.000501

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000213

Gnomad4 SAS exome AF: 0.000393

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74466

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.00114

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs763993290; hg19: chr13-37422717;