rs4776343

Positions:

• chr15-67167472-G-A

Variant summary

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

The NM_005902.4(SMAD3):​c.607+619G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 152,236 control chromosomes in the GnomAD database, including 304 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 0.055 (304 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15

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=-0.73).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.092 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.607+619G>A		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.607+619G>A		intron_variant		1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8336 AN: 152118 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0956

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0579

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

GnomAD4 genome AF: 0.0549 AC: 8358 AN: 152236 Hom.: 304 Cov.: 32 AF XY: 0.0542 AC XY: 4036 AN XY: 74424

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.0960

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.0360

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.0719

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.0619 Hom.: 42

Bravo AF: 0.0580

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.070
DANN	Benign	0.84

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: rs4776343; hg19: chr15-67459810;