chr15-67146869-T-G

Variant names:

• chr15-67146869-T-G
• rs2289263
• NM_005902.4:c.207-18026T>G

Variant summary

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

The NM_005902.4(SMAD3):​c.207-18026T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 151,828 control chromosomes in the GnomAD database, including 14,659 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 0.43 (14648 hom., cov: 31)
  • Exomes 𝑓: 0.53 (11 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.954
• Publications: 25 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_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.207-18026T>G		intron	N/A	NP_005893.1
	SMAD3	NM_001407011.1		c.207-18026T>G		intron	N/A	NP_001393940.1
	SMAD3	NM_001145103.2		c.74+8769T>G		intron	N/A	NP_001138575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.207-18026T>G		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.74+8769T>G		intron	N/A	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.-109-18026T>G		intron	N/A	ENSP00000437757.2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65745 AN: 151648 Hom.: 14646 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.530 AC: 35 AN: 66 Hom.: 11 Cov.: 0 AF XY: 0.537 AC XY: 29 AN XY: 54

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 4 AN: 4

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.519 AC: 27 AN: 52

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.433 AC: 65786 AN: 151762 Hom.: 14648 Cov.: 31 AF XY: 0.439 AC XY: 32525 AN XY: 74164

African (AFR) AF: 0.317 AC: 13093 AN: 41352

American (AMR) AF: 0.466 AC: 7110 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1783 AN: 3468

East Asian (EAS) AF: 0.377 AC: 1937 AN: 5134

South Asian (SAS) AF: 0.435 AC: 2087 AN: 4802

European-Finnish (FIN) AF: 0.563 AC: 5948 AN: 10564

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32180 AN: 67878

Other (OTH) AF: 0.467 AC: 981 AN: 2102

Alfa AF: 0.463 Hom.: 25579

Bravo AF: 0.418

Asia WGS AF: 0.435 AC: 1513 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	7.6
DANN	Benign	0.79
PhyloP100		0.95
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: rs2289263; hg19: chr15-67439207;