15-67142737-G-A

Variant names:

• chr15-67142737-G-A
• rs745103
• NM_005902.4:c.207-22158G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(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 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592
• Publications: 34 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-AS1 (HGNC:56692): (SMAD3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.207-22158G>A		intron	N/A	NP_005893.1
	SMAD3-AS1	NR_186224.1		n.469C>T		non_coding_transcript_exon	Exon 3 of 3
	SMAD3	NM_001407011.1		c.207-22158G>A		intron	N/A	NP_001393940.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.207-22158G>A		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.74+4637G>A		intron	N/A	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.-110+16753G>A		intron	N/A	ENSP00000437757.2

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

GnomAD2 exomes AF: 0.496 AC: 32043 AN: 64610 AF XY: 0.509

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 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

African (AFR) AF: 0.444 AC: 2020 AN: 4550

American (AMR) AF: 0.406 AC: 5824 AN: 14332

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 2966 AN: 6264

East Asian (EAS) AF: 0.399 AC: 2125 AN: 5328

South Asian (SAS) AF: 0.579 AC: 25821 AN: 44596

European-Finnish (FIN) AF: 0.491 AC: 4836 AN: 9846

Middle Eastern (MID) AF: 0.586 AC: 1313 AN: 2242

European-Non Finnish (NFE) AF: 0.543 AC: 55846 AN: 102846

Other (OTH) AF: 0.514 AC: 4876 AN: 9478

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

African (AFR) AF: 0.450 AC: 18647 AN: 41412

American (AMR) AF: 0.484 AC: 7399 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1633 AN: 3466

East Asian (EAS) AF: 0.409 AC: 2114 AN: 5164

South Asian (SAS) AF: 0.571 AC: 2746 AN: 4810

European-Finnish (FIN) AF: 0.496 AC: 5236 AN: 10558

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36812 AN: 67964

Other (OTH) AF: 0.511 AC: 1080 AN: 2112

Alfa AF: 0.520 Hom.: 39218

Bravo AF: 0.496

Asia WGS AF: 0.490 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.51
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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