15-67184430-C-T

Variant names:

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

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: 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.872-297C>T		intron_variant	Intron 6 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.872-297C>T		intron_variant	Intron 6 of 8	1	NM_005902.4	ENSP00000332973.4

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

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;