rs28410524

Positions:

• chr15-67190358-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1155-55A>G		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1155-55A>G		intron_variant		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

Gnomad4 AFR exome AF: 0.0624

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.00371

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.00585

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

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0132

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00921 Hom.: 8

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.16
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

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