15-67146248-C-T

Variant names:

• chr15-67146248-C-T
• rs750766
• NM_005902.4:c.207-18647C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001407011.1(SMAD3):​c.207-18647C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 152,134 control chromosomes in the GnomAD database, including 16,104 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 0.46 (16103 hom., cov: 33)
  • Exomes 𝑓: 0.43 (1 hom.)
• Consequence: SMAD3 NM_001407011.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 13 publications found

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]

SMAD3-AS1 (HGNC:56692): (SMAD3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407011.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.207-18647C>T		intron	N/A	NP_005893.1
	SMAD3	NM_001407011.1		c.207-18647C>T		intron	N/A	NP_001393940.1
	SMAD3	NM_001145103.2		c.74+8148C>T		intron	N/A	NP_001138575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.207-18647C>T		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.74+8148C>T		intron	N/A	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.-109-18647C>T		intron	N/A	ENSP00000437757.2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69734 AN: 152002 Hom.: 16100 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.476

GnomAD4 exome AF: 0.429 AC: 6 AN: 14 Hom.: 1 AF XY: 0.417 AC XY: 5 AN XY: 12

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 4 AN: 8

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.459 AC: 69761 AN: 152120 Hom.: 16103 Cov.: 33 AF XY: 0.463 AC XY: 34432 AN XY: 74342

African (AFR) AF: 0.409 AC: 16954 AN: 41498

American (AMR) AF: 0.471 AC: 7202 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1782 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1932 AN: 5178

South Asian (SAS) AF: 0.433 AC: 2090 AN: 4828

European-Finnish (FIN) AF: 0.559 AC: 5898 AN: 10550

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.474 AC: 32219 AN: 67980

Other (OTH) AF: 0.480 AC: 1014 AN: 2114

Alfa AF: 0.455 Hom.: 12710

Bravo AF: 0.447

Asia WGS AF: 0.438 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.63
DANN	Benign	0.48
PhyloP100		-0.0030
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs750766; hg19: chr15-67438586;