rs7181556

Variant names:

• chr15-67184430-C-T
• rs7181556
• NM_005902.4:c.872-297C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-67184430-C-T
• chr15-67184430-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005902.4(SMAD3):​c.872-297C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,046 control chromosomes in the GnomAD database, including 4,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (4316 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.417
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-67184430-C-T is Benign according to our data. Variant chr15-67184430-C-T is described in ClinVar as Benign. ClinVar VariationId is 683848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 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.872-297C>T		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.872-297C>T		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.740-297C>T		intron	N/A	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.872-297C>T		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.740-297C>T		intron	N/A	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.557-297C>T		intron	N/A	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34020 AN: 151928 Hom.: 4311 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.247

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.224 AC: 34060 AN: 152046 Hom.: 4316 Cov.: 32 AF XY: 0.228 AC XY: 16969 AN XY: 74296

African (AFR) AF: 0.119 AC: 4925 AN: 41500

American (AMR) AF: 0.327 AC: 4992 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3466

East Asian (EAS) AF: 0.476 AC: 2454 AN: 5152

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4818

European-Finnish (FIN) AF: 0.215 AC: 2266 AN: 10554

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16155 AN: 67960

Other (OTH) AF: 0.249 AC: 526 AN: 2112

Alfa AF: 0.211 Hom.: 1403

Bravo AF: 0.229

Asia WGS AF: 0.342 AC: 1188 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.6
DANN	Benign	0.48
PhyloP100		-0.42
PromoterAI		-0.015	Neutral
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: rs7181556; hg19: chr15-67476768;