13-36845100-ATG-A

Variant summary

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

The NM_001127217.3(SMAD9):c.*3574_*3575del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 145,934 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMAD9 NM_001127217.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.685

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 sas. gnomad4 allele frequency = 0.0134 (1954/145934) while in subpopulation SAS AF= 0.0468 (219/4678). AF 95% confidence interval is 0.0417. There are 22 homozygotes in gnomad4. There are 984 alleles in male gnomad4 subpopulation. Median coverage is 30. 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 1955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.*3574_*3575del		3_prime_UTR_variant	7/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.*3574_*3575del		3_prime_UTR_variant	7/7	5	NM_001127217.3	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 1955 AN: 145824 Hom.: 22 Cov.: 30

Gnomad AFR AF: 0.00624

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0463

Gnomad EAS AF: 0.00177

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.00540

Gnomad MID AF: 0.0392

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0301

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0134 AC: 1954 AN: 145934 Hom.: 22 Cov.: 30 AF XY: 0.0138 AC XY: 984 AN XY: 71076

Gnomad4 AFR AF: 0.00625

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0463

Gnomad4 EAS AF: 0.00177

Gnomad4 SAS AF: 0.0468

Gnomad4 FIN AF: 0.00540

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0293

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

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Computational scores

Source: dbNSFP v4.3

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: rs201352307; hg19: chr13-37419237;