rs4776342

Positions:

• chr15-67126053-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.207-38842A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 779,918 control chromosomes in the GnomAD database, including 24,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7883 hom., cov: 32)
  • Exomes 𝑓: 0.22 (16517 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.96

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-67126053-A-G is Benign according to our data. Variant chr15-67126053-A-G is described in ClinVar as [Benign]. Clinvar id is 1256793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-38842A>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.207-38842A>G		intron_variant		1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46386 AN: 151922 Hom.: 7868 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.224 AC: 140544 AN: 627878 Hom.: 16517 AF XY: 0.224 AC XY: 65680 AN XY: 293228

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.305 AC: 46443 AN: 152040 Hom.: 7883 Cov.: 32 AF XY: 0.308 AC XY: 22890 AN XY: 74322

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.606

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.324

Alfa AF: 0.254 Hom.: 1082

Bravo AF: 0.324

Asia WGS AF: 0.488 AC: 1694 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	clinical testing	GeneDx	May 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.059
DANN	Benign	0.25

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: rs4776342; hg19: chr15-67418391;