15-67066127-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005902.4(SMAD3):c.-28C>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 0.00294 in 1,550,850 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 65 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 39 hom. )

Consequence

SMAD3
NM_005902.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.134

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 15-67066127-C-T is Benign according to our data. Variant chr15-67066127-C-T is described in ClinVar as [Benign]. Clinvar id is 139214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 9	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0
SMAD3	NM_001407011.1 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 10		NP_001393940.1
SMAD3	NM_001407012.1 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 8		NP_001393941.1
SMAD3	NM_001407013.1 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD3	ENST00000327367 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 9	1	NM_005902.4	ENSP00000332973.4	P84022-1
SMAD3	ENST00000560424 link	c.-28C>T	5_prime_UTR_variant	Exon 1 of 10	3		ENSP00000455540.2	H3BQ00
SMAD3	ENST00000559460.6 link	c.-110+2183C>T	intron_variant	Intron 1 of 8	4		ENSP00000453082.2	H0YL71

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2307

AN:

151404

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0533

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00499

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.000266

Gnomad OTH

AF:

0.00481

GnomAD3 exomes

AF:

0.00334

AC:

535

AN:

160088

Hom.:

AF XY:

0.00279

AC XY:

241

AN XY:

86316

show subpopulations

Gnomad AFR exome

AF:

0.0560

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000423

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000323

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00161

AC:

2258

AN:

1399336

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1022

AN XY:

691456

show subpopulations

Gnomad4 AFR exome

AF:

0.0547

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.000113

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.0152

AC:

2308

AN:

151514

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1067

AN XY:

74062

show subpopulations

Gnomad4 AFR

AF:

0.0532

Gnomad4 AMR

AF:

0.00498

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000266

Gnomad4 OTH

AF:

0.00476

Alfa

AF:

0.00829

Hom.:

Bravo

AF:

0.0174

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 21, 2013

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. -

Loeys-Dietz syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aneurysm-osteoarthritis syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.34

CADD

Benign

DANN

Uncertain

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over