rs11633026

Variant names:

• chr15-67065420-C-T
• rs11633026
• ENST00000559460.6:c.-110+1476C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000559460.6(SMAD3):​c.-110+1476C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 151,098 control chromosomes in the GnomAD database, including 1,679 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 0.14 (1679 hom., cov: 31)
• Consequence: SMAD3 ENST00000559460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 3 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.-735C>T		upstream_gene_variant		ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.-735C>T		upstream_gene_variant			NP_001393940.1
SMAD3	NM_001407012.1	c.-735C>T		upstream_gene_variant			NP_001393941.1
SMAD3	NM_001407013.1	c.-735C>T		upstream_gene_variant			NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.-735C>T		upstream_gene_variant		1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20465 AN: 150990 Hom.: 1663 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0342

Gnomad AMR AF: 0.0946

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.127

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.136 AC: 20531 AN: 151098 Hom.: 1679 Cov.: 31 AF XY: 0.136 AC XY: 10027 AN XY: 73838

African (AFR) AF: 0.207 AC: 8582 AN: 41378

American (AMR) AF: 0.0945 AC: 1435 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3466

East Asian (EAS) AF: 0.191 AC: 969 AN: 5068

South Asian (SAS) AF: 0.186 AC: 896 AN: 4820

European-Finnish (FIN) AF: 0.0877 AC: 894 AN: 10198

Middle Eastern (MID) AF: 0.0972 AC: 28 AN: 288

European-Non Finnish (NFE) AF: 0.104 AC: 7018 AN: 67692

Other (OTH) AF: 0.133 AC: 278 AN: 2098

Alfa AF: 0.112 Hom.: 141

Bravo AF: 0.137

Asia WGS AF: 0.195 AC: 670 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.94
PhyloP100		0.15
PromoterAI		-0.075	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11633026; hg19: chr15-67357758;