chr15-67091812-C-T

Variant names:

• chr15-67091812-C-T
• rs4776339
• NM_005902.4:c.206+25452C>T

Variant summary

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

The NM_005902.4(SMAD3):​c.206+25452C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,914 control chromosomes in the GnomAD database, including 17,024 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 0.45 (17024 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347

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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.206+25452C>T		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.206+25452C>T		intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1	c.206+25452C>T		intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1	c.206+25452C>T		intron_variant	Intron 1 of 7		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+25452C>T		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68421 AN: 151796 Hom.: 17026 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.450 AC: 68429 AN: 151914 Hom.: 17024 Cov.: 32 AF XY: 0.459 AC XY: 34112 AN XY: 74242

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.489

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.699

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.481

Alfa AF: 0.504 Hom.: 18932

Bravo AF: 0.436

Asia WGS AF: 0.570 AC: 1982 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.73

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: rs4776339; hg19: chr15-67384150;