15-67184632-T-C

Variant names:

• chr15-67184632-T-C
• rs2289790
• NM_005902.4:c.872-95T>C

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.872-95T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,472,636 control chromosomes in the GnomAD database, including 49,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4440 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45167 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99

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=-0.87).
• BP6: Variant 15-67184632-T-C is Benign according to our data. Variant chr15-67184632-T-C is described in ClinVar as [Benign]. Clinvar id is 673140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.872-95T>C		intron_variant	Intron 6 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.872-95T>C		intron_variant	Intron 6 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34846 AN: 152100 Hom.: 4435 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.254 AC: 335957 AN: 1320416 Hom.: 45167 AF XY: 0.255 AC XY: 169242 AN XY: 664028

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.498

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.229 AC: 34894 AN: 152220 Hom.: 4440 Cov.: 32 AF XY: 0.234 AC XY: 17399 AN XY: 74424

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.255

Alfa AF: 0.235 Hom.: 767

Bravo AF: 0.235

Asia WGS AF: 0.344 AC: 1198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.18
DANN	Benign	0.75

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: rs2289790; hg19: chr15-67476970;