rs745103

Positions:

• chr15-67142737-G-A
• chr15-67142737-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000327367.9(SMAD3):​c.207-22158G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 351,472 control chromosomes in the GnomAD database, including 48,136 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (19424 hom., cov: 32)
  • Exomes 𝑓: 0.53 (28712 hom.)
• Consequence: SMAD3 ENST00000327367.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592

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-AS1 (HGNC:56692): (SMAD3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-22158G>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.207-22158G>A		intron_variant		1	NM_005902.4	ENSP00000332973	P1
SMAD3-AS1	ENST00000558463.1	n.469C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76292 AN: 151872 Hom.: 19409 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.496 AC: 32043 AN: 64610 Hom.: 8180 AF XY: 0.509 AC XY: 17979 AN XY: 35342

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.397

Gnomad SAS exome AF: 0.573

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.530 AC: 105627 AN: 199482 Hom.: 28712 Cov.: 0 AF XY: 0.538 AC XY: 60442 AN XY: 112388

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.502 AC: 76349 AN: 151990 Hom.: 19424 Cov.: 32 AF XY: 0.501 AC XY: 37208 AN XY: 74294

Gnomad4 AFR AF: 0.450

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.471

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.571

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.511

Alfa AF: 0.523 Hom.: 28631

Bravo AF: 0.496

Asia WGS AF: 0.490 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.51

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: rs745103; hg19: chr15-67435075; COSMIC: COSV59285747;