15-67174541-T-G

Variant names:

• chr15-67174541-T-G
• rs2278545
• NM_005902.4:c.658+3937T>G

Variant summary

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

The NM_005902.4(SMAD3):​c.658+3937T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,234 control chromosomes in the GnomAD database, including 58,376 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 0.87 (58280 hom., cov: 30)
  • Exomes 𝑓: 0.90 (96 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.658+3937T>G		intron_variant	Intron 5 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.658+3937T>G		intron_variant	Intron 5 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.875 AC: 132880 AN: 151876 Hom.: 58233 Cov.: 30

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.896 AC: 215 AN: 240 Hom.: 96 Cov.: 0 AF XY: 0.897 AC XY: 156 AN XY: 174

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.722

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.875

GnomAD4 genome AF: 0.875 AC: 132983 AN: 151994 Hom.: 58280 Cov.: 30 AF XY: 0.873 AC XY: 64822 AN XY: 74250

Gnomad4 AFR AF: 0.860

Gnomad4 AMR AF: 0.913

Gnomad4 ASJ AF: 0.875

Gnomad4 EAS AF: 0.763

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.890

Gnomad4 OTH AF: 0.885

Alfa AF: 0.883 Hom.: 30299

Bravo AF: 0.882

Asia WGS AF: 0.783 AC: 2724 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.9
DANN	Benign	0.58

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: rs2278545; hg19: chr15-67466879;