15-67093131-C-G

Variant summary

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

The NM_005902.4(SMAD3):c.206+26771C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,048 control chromosomes in the GnomAD database, including 24,185 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 0.56 (24185 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110

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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.206+26771C>G		intron_variant		ENST00000327367.9
SMAD3	NM_001407011.1	c.206+26771C>G		intron_variant
SMAD3	NM_001407012.1	c.206+26771C>G		intron_variant
SMAD3	NM_001407013.1	c.206+26771C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+26771C>G		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84990 AN: 151930 Hom.: 24178 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.559 AC: 85029 AN: 152048 Hom.: 24185 Cov.: 33 AF XY: 0.565 AC XY: 41983 AN XY: 74328

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.580

Alfa AF: 0.438 Hom.: 1206

Bravo AF: 0.554

Asia WGS AF: 0.657 AC: 2284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.9
Dann	Benign	0.63
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: rs1465841; hg19: chr15-67385469;