rs55678244

chr15-67187532-A-Cchr15-67187532-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005902.4(SMAD3):c.1154+23A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,614,058 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign no assertion criteria provided B:2
• Conservation: PhyloP100: -0.0910

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-67187532-A-C is Benign according to our data. Variant chr15-67187532-A-C is described in ClinVar as [Benign]. Clinvar id is 1284999.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-67187532-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00279 (425/152306) while in subpopulation NFE AF= 0.00391 (266/68022). AF 95% confidence interval is 0.00352. There are 1 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 425 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.1154+23A>C		intron_variant		ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.1154+23A>C		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00317 AC: 797 AN: 251418 Hom.: 2 AF XY: 0.00324 AC XY: 440 AN XY: 135880

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00392 AC: 5727 AN: 1461752 Hom.: 18 Cov.: 31 AF XY: 0.00388 AC XY: 2819 AN XY: 727182

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.00656

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74476

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00734

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0050
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs55678244; hg19: chr15-67479870;