rs1375423378

chr13-36865543-CTA-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001127217.3(SMAD9):c.995_996del(p.Ile332ArgfsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMAD9 NM_001127217.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.995_996del	p.Ile332ArgfsTer20	frameshift_variant	5/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.995_996del	p.Ile332ArgfsTer20	frameshift_variant	5/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.884_885del	p.Ile295ArgfsTer20	frameshift_variant	4/6	1
SMAD9	ENST00000399275.7	c.*594_*595del		3_prime_UTR_variant, NMD_transcript_variant	4/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251428 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459838 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2017

The p.Ile332fs variant in SMAD9 has not been previously reported in individuals with pulmonary disease or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 332 and leads to a premature termination codon 20 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. However, it is unclear if loss of function is a mechanism of disease in this gene. In summary, the clinical significance of the p.Ile332fs variant is uncerta in. -

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: rs1375423378; hg19: chr13-37439680;