rs16950635

Positions:

• chr15-67125867-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000540846.6(SMAD3):​c.-227G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 985,320 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (611 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1001 hom.)
• Consequence: SMAD3 ENST00000540846.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54

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=-0.77).
• BP6: Variant 15-67125867-G-A is Benign according to our data. Variant chr15-67125867-G-A is described in ClinVar as [Benign]. Clinvar id is 1288852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-39028G>A		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-39028G>A		intron_variant		1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes AF: 0.0765 AC: 11626 AN: 152036 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0464

Gnomad OTH AF: 0.0796

GnomAD4 exome AF: 0.0441 AC: 36767 AN: 833166 Hom.: 1001 Cov.: 30 AF XY: 0.0440 AC XY: 16912 AN XY: 384756

Gnomad4 AFR exome AF: 0.0984

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0662

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0766 AC: 11649 AN: 152154 Hom.: 611 Cov.: 32 AF XY: 0.0790 AC XY: 5876 AN XY: 74392

Gnomad4 AFR AF: 0.0901

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0464

Gnomad4 OTH AF: 0.0802

Alfa AF: 0.0597 Hom.: 362

Bravo AF: 0.0831

Asia WGS AF: 0.171 AC: 592 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	Oct 07, 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	-0.77
CADD	Benign	17
DANN	Benign	0.79

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: rs16950635; hg19: chr15-67418205;