rs28410524

Variant names:

• chr15-67190358-A-G
• rs28410524
• NM_005902.4:c.1155-55A>G

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.1155-55A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,548,022 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (72 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.09
• Publications: 4 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=-0.86).
• BP6: Variant 15-67190358-A-G is Benign according to our data. Variant chr15-67190358-A-G is described in ClinVar as Benign. ClinVar VariationId is 1264473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1155-55A>G		intron_variant	Intron 8 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1155-55A>G		intron_variant	Intron 8 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2731 AN: 151918 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00259 AC: 3621 AN: 1395986 Hom.: 72 AF XY: 0.00243 AC XY: 1695 AN XY: 697880

African (AFR) AF: 0.0624 AC: 2011 AN: 32222

American (AMR) AF: 0.00265 AC: 118 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 34 AN: 25664

East Asian (EAS) AF: 0.0146 AC: 575 AN: 39406

South Asian (SAS) AF: 0.00371 AC: 315 AN: 84920

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53106

Middle Eastern (MID) AF: 0.00372 AC: 21 AN: 5648

European-Non Finnish (NFE) AF: 0.000193 AC: 203 AN: 1052166

Other (OTH) AF: 0.00585 AC: 341 AN: 58270

GnomAD4 genome AF: 0.0182 AC: 2760 AN: 152036 Hom.: 105 Cov.: 32 AF XY: 0.0167 AC XY: 1239 AN XY: 74342

African (AFR) AF: 0.0612 AC: 2535 AN: 41448

American (AMR) AF: 0.00530 AC: 81 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0132 AC: 68 AN: 5162

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67960

Other (OTH) AF: 0.0190 AC: 40 AN: 2102

Alfa AF: 0.00844 Hom.: 14

Bravo AF: 0.0204

Asia WGS AF: 0.0570 AC: 196 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.16
DANN	Benign	0.43
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

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: rs28410524; hg19: chr15-67482696; COSMIC: COSV59284460; COSMIC: COSV59284460;