15-67190938-C-T

Variant names:

• chr15-67190938-C-T
• rs8025774
• NM_005902.4:c.*402C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005902.4(SMAD3):​c.*402C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 292,476 control chromosomes in the GnomAD database, including 9,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3792 hom., cov: 31)
  • Exomes 𝑓: 0.25 (5301 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.71
• Publications: 26 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: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-67190938-C-T is Benign according to our data. Variant chr15-67190938-C-T is described in ClinVar as Benign. ClinVar VariationId is 316873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 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.*402C>T		3_prime_UTR	Exon 9 of 9	NP_005893.1
	SMAD3	NM_001407011.1		c.*402C>T		3_prime_UTR	Exon 10 of 10	NP_001393940.1
	SMAD3	NM_001145103.2		c.*402C>T		3_prime_UTR	Exon 9 of 9	NP_001138575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.*402C>T		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4
	SMAD3	ENST00000558763.1	TSL:2	n.1374C>T		non_coding_transcript_exon	Exon 2 of 2
	SMAD3	ENST00000680689.1		n.1383C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30525 AN: 151996 Hom.: 3791 Cov.: 31

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.237

GnomAD4 exome AF: 0.252 AC: 35441 AN: 140362 Hom.: 5301 Cov.: 0 AF XY: 0.253 AC XY: 17239 AN XY: 68118

African (AFR) AF: 0.0735 AC: 487 AN: 6622

American (AMR) AF: 0.321 AC: 2156 AN: 6712

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 2232 AN: 6678

East Asian (EAS) AF: 0.472 AC: 7195 AN: 15228

South Asian (SAS) AF: 0.259 AC: 1905 AN: 7360

European-Finnish (FIN) AF: 0.149 AC: 302 AN: 2026

Middle Eastern (MID) AF: 0.271 AC: 195 AN: 720

European-Non Finnish (NFE) AF: 0.220 AC: 18721 AN: 85158

Other (OTH) AF: 0.228 AC: 2248 AN: 9858

GnomAD4 genome AF: 0.201 AC: 30544 AN: 152114 Hom.: 3792 Cov.: 31 AF XY: 0.206 AC XY: 15286 AN XY: 74364

African (AFR) AF: 0.0736 AC: 3058 AN: 41542

American (AMR) AF: 0.316 AC: 4823 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.461 AC: 2372 AN: 5150

South Asian (SAS) AF: 0.284 AC: 1365 AN: 4814

European-Finnish (FIN) AF: 0.181 AC: 1921 AN: 10596

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.222 AC: 15080 AN: 67956

Other (OTH) AF: 0.238 AC: 502 AN: 2110

Alfa AF: 0.224 Hom.: 5812

Bravo AF: 0.207

Asia WGS AF: 0.333 AC: 1157 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aneurysm-osteoarthritis syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.69
DANN	Benign	0.68
PhyloP100		-1.7
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: rs8025774; hg19: chr15-67483276; COSMIC: COSV107381609; COSMIC: COSV107381609;