15-67194045-A-G

Variant names:

• chr15-67194045-A-G
• rs11556090
• NM_005902.4:c.*3509A>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.*3509A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 232,978 control chromosomes in the GnomAD database, including 27,734 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 0.49 (18332 hom., cov: 32)
  • Exomes 𝑓: 0.46 (9402 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 19 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 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.*3509A>G		3_prime_UTR	Exon 9 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.*3509A>G		3_prime_UTR	Exon 10 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.*3509A>G		3_prime_UTR	Exon 9 of 9	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.*3509A>G		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000558739.2	TSL:3	c.*3509A>G		3_prime_UTR	Exon 9 of 9	ENSP00000453684.2	P84022-3
	SMAD3	ENST00000559460.6	TSL:4	c.*3509A>G		3_prime_UTR	Exon 9 of 9	ENSP00000453082.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73745 AN: 151934 Hom.: 18329 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.462 AC: 37356 AN: 80926 Hom.: 9402 Cov.: 0 AF XY: 0.460 AC XY: 17136 AN XY: 37220

African (AFR) AF: 0.508 AC: 1971 AN: 3880

American (AMR) AF: 0.333 AC: 829 AN: 2490

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 2227 AN: 5112

East Asian (EAS) AF: 0.158 AC: 1813 AN: 11508

South Asian (SAS) AF: 0.297 AC: 208 AN: 700

European-Finnish (FIN) AF: 0.625 AC: 45 AN: 72

Middle Eastern (MID) AF: 0.478 AC: 234 AN: 490

European-Non Finnish (NFE) AF: 0.534 AC: 26684 AN: 49934

Other (OTH) AF: 0.496 AC: 3345 AN: 6740

GnomAD4 genome AF: 0.485 AC: 73767 AN: 152052 Hom.: 18332 Cov.: 32 AF XY: 0.478 AC XY: 35521 AN XY: 74322

African (AFR) AF: 0.509 AC: 21105 AN: 41466

American (AMR) AF: 0.359 AC: 5478 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3468

East Asian (EAS) AF: 0.191 AC: 988 AN: 5168

South Asian (SAS) AF: 0.336 AC: 1620 AN: 4820

European-Finnish (FIN) AF: 0.526 AC: 5564 AN: 10572

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.528 AC: 35890 AN: 67976

Other (OTH) AF: 0.457 AC: 965 AN: 2110

Alfa AF: 0.475 Hom.: 6392

Bravo AF: 0.472

Asia WGS AF: 0.264 AC: 921 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.38
PhyloP100		-1.5
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: rs11556090; hg19: chr15-67486383;