rs774470515

Variant names:

• chr15-67184845-C-T
• rs774470515
• NM_005902.4:c.990C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005902.4(SMAD3):​c.990C>T​(p.Thr330Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: SMAD3 NM_005902.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.25
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 15-67184845-C-T is Benign according to our data. Variant chr15-67184845-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000952 (139/1460814) while in subpopulation MID AF = 0.000203 (1/4920). AF 95% confidence interval is 0.000092. There are 0 homozygotes in GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 AD gene.

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.990C>T	p.Thr330Thr	synonymous	Exon 7 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.990C>T	p.Thr330Thr	synonymous	Exon 7 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.858C>T	p.Thr286Thr	synonymous	Exon 7 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.990C>T	p.Thr330Thr	synonymous	Exon 7 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.858C>T	p.Thr286Thr	synonymous	Exon 7 of 9	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.675C>T	p.Thr225Thr	synonymous	Exon 7 of 9	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251362 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000952 AC: 139 AN: 1460814 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 75 AN XY: 726716

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4920

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1112000

Other (OTH) AF: 0.000116 AC: 7 AN: 60290

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000637 Hom.: 0

Bravo AF: 0.0000869

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Aneurysm-osteoarthritis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.4
DANN	Benign	0.72
PhyloP100		-3.3
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774470515; hg19: chr15-67477183; COSMIC: COSV107381544;