rs2118611

Positions:

• chr15-67109128-T-C

Variant summary

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

The NM_005902.4(SMAD3):​c.206+42768T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 152,184 control chromosomes in the GnomAD database, including 4,845 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 0.24 (4845 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.206+42768T>C		intron_variant		ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+42768T>C		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36098 AN: 152066 Hom.: 4836 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.237 AC: 36123 AN: 152184 Hom.: 4845 Cov.: 33 AF XY: 0.244 AC XY: 18182 AN XY: 74404

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.527

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.250

Alfa AF: 0.243 Hom.: 891

Bravo AF: 0.250

Asia WGS AF: 0.399 AC: 1385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.59

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: rs2118611; hg19: chr15-67401466;