15-67066132-C-T

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.-23C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,557,014 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (132 hom.)
• Consequence: SMAD3 NM_005902.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.27

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=-0.54).
• BP6: Variant 15-67066132-C-T is Benign according to our data. Variant chr15-67066132-C-T is described in ClinVar as [Benign]. Clinvar id is 139215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67066132-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.-23C>T		5_prime_UTR_variant	1/9	ENST00000327367.9
SMAD3	NM_001407011.1	c.-23C>T		5_prime_UTR_variant	1/10
SMAD3	NM_001407012.1	c.-23C>T		5_prime_UTR_variant	1/8
SMAD3	NM_001407013.1	c.-23C>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.-23C>T		5_prime_UTR_variant	1/9	1	NM_005902.4	P1
SMAD3	ENST00000560424.2	c.-23C>T		5_prime_UTR_variant	1/10	3
SMAD3	ENST00000559460.6	c.-110+2188C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 545 AN: 151690 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.000380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000516

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00856 AC: 1427 AN: 166720 Hom.: 30 AF XY: 0.00935 AC XY: 842 AN XY: 90024

Gnomad AFR exome AF: 0.000792

Gnomad AMR exome AF: 0.000342

Gnomad ASJ exome AF: 0.000588

Gnomad EAS exome AF: 0.0628

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.000667

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00358 AC: 5032 AN: 1405214 Hom.: 132 Cov.: 29 AF XY: 0.00424 AC XY: 2948 AN XY: 694662

Gnomad4 AFR exome AF: 0.000375

Gnomad4 AMR exome AF: 0.000348

Gnomad4 ASJ exome AF: 0.000555

Gnomad4 EAS exome AF: 0.0644

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.000909

Gnomad4 NFE exome AF: 0.000372

Gnomad4 OTH exome AF: 0.00643

GnomAD4 genome AF: 0.00362 AC: 549 AN: 151800 Hom.: 15 Cov.: 32 AF XY: 0.00462 AC XY: 343 AN XY: 74202

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.0645

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.000380

Gnomad4 NFE AF: 0.000516

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00328

Asia WGS AF: 0.0530 AC: 183 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2013

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. -

Loeys-Dietz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Aneurysm-osteoarthritis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	16
Dann	Benign	0.96

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: rs36221703; hg19: chr15-67358470;