15-67135996-T-C

Position:

• chr15-67135996-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.207-28899T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,006 control chromosomes in the GnomAD database, including 27,900 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 0.60 (27900 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175

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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.207-28899T>C		intron_variant		ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-28899T>C		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91256 AN: 151888 Hom.: 27871 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.631

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

GnomAD4 genome AF: 0.601 AC: 91332 AN: 152006 Hom.: 27900 Cov.: 32 AF XY: 0.611 AC XY: 45368 AN XY: 74294

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.695

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.898

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.589

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.635

Alfa AF: 0.573 Hom.: 51021

Bravo AF: 0.607

Asia WGS AF: 0.820 AC: 2853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.77

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: rs2118610; hg19: chr15-67428334;