chr15-67065340-G-A

Position:

• chr15-67065340-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000559460.6(SMAD3):​c.-110+1396G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 151,966 control chromosomes in the GnomAD database, including 1,147 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1146 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: SMAD3 ENST00000559460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.67065340G>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000559460.6	c.-110+1396G>A		intron_variant		4		ENSP00000453082.2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17629 AN: 151728 Hom.: 1147 Cov.: 32

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.119 AC: 14 AN: 118 Hom.: 1 AF XY: 0.140 AC XY: 12 AN XY: 86

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.116 AC: 17621 AN: 151848 Hom.: 1146 Cov.: 32 AF XY: 0.120 AC XY: 8884 AN XY: 74230

Gnomad4 AFR AF: 0.0669

Gnomad4 AMR AF: 0.0987

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.111

Alfa AF: 0.121 Hom.: 106

Bravo AF: 0.106

Asia WGS AF: 0.138 AC: 478 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.96

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs36222034; hg19: chr15-67357678;