15-67066040-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_005902.4(SMAD3):​c.-115C>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 0.0000439 in 546,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SMAD3
NM_005902.4 5_prime_UTR

Scores

1
1

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.64
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
Variant 15-67066040-C-T is Benign according to our data. Variant chr15-67066040-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 316858.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000113 (17/150578) while in subpopulation EAS AF= 0.00299 (15/5024). AF 95% confidence interval is 0.00184. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMAD3NM_005902.4 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/9 ENST00000327367.9
SMAD3NM_001407011.1 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/10
SMAD3NM_001407012.1 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/8
SMAD3NM_001407013.1 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMAD3ENST00000327367.9 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/91 NM_005902.4 P1P84022-1
SMAD3ENST00000560424.2 linkuse as main transcriptc.-115C>T 5_prime_UTR_variant 1/103
SMAD3ENST00000559460.6 linkuse as main transcriptc.-110+2096C>T intron_variant 4

Frequencies

GnomAD3 genomes
AF:
0.000113
AC:
17
AN:
150468
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00298
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000177
AC:
7
AN:
396420
Hom.:
0
Cov.:
6
AF XY:
0.0000147
AC XY:
3
AN XY:
204344
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000146
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000687
Gnomad4 OTH exome
AF:
0.0000982
GnomAD4 genome
AF:
0.000113
AC:
17
AN:
150578
Hom.:
0
Cov.:
31
AF XY:
0.000122
AC XY:
9
AN XY:
73600
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00299
Gnomad4 SAS
AF:
0.000416
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Loeys-Dietz syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Benign
19
DANN
Uncertain
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs556470157; hg19: chr15-67358378; API