rs36222034

Variant names:

• chr15-67065340-G-A
• rs36222034
• ENST00000559460.6:c.-110+1396G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

SMAD3-DT (HGNC:56759): (SMAD3 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000559460.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000559460.6	TSL:4	c.-110+1396G>A		intron	N/A	ENSP00000453082.2	P84022-3
	SMAD3-DT	ENST00000636067.1	TSL:5	n.-72C>T		upstream_gene	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.106 AC: 11 AN: 104

Other (OTH) AF: 1.00 AC: 2 AN: 2

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

African (AFR) AF: 0.0669 AC: 2777 AN: 41522

American (AMR) AF: 0.0987 AC: 1508 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3468

East Asian (EAS) AF: 0.147 AC: 750 AN: 5106

South Asian (SAS) AF: 0.219 AC: 1053 AN: 4814

European-Finnish (FIN) AF: 0.163 AC: 1713 AN: 10504

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.133 AC: 9007 AN: 67838

Other (OTH) AF: 0.111 AC: 233 AN: 2108

Alfa AF: 0.127 Hom.: 162

Bravo AF: 0.106

Asia WGS AF: 0.138 AC: 478 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.047
PromoterAI		0.074	Neutral

Splicing

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

Other links and lift over

dbSNP: rs36222034; hg19: chr15-67357678;