rs6494633

Positions:

• chr15-67130968-C-T

Variant summary

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

The NM_005902.4(SMAD3):​c.207-33927C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 152,016 control chromosomes in the GnomAD database, including 11,210 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 0.37 (11210 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.361

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-33927C>T		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-33927C>T		intron_variant		1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56960 AN: 151898 Hom.: 11205 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.354

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

GnomAD4 genome AF: 0.375 AC: 56993 AN: 152016 Hom.: 11210 Cov.: 32 AF XY: 0.367 AC XY: 27270 AN XY: 74302

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.351

Alfa AF: 0.419 Hom.: 18489

Bravo AF: 0.366

Asia WGS AF: 0.174 AC: 606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6494633; hg19: chr15-67423306;