chr4-145540026-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005900.3(SMAD1):​c.623C>T​(p.Thr208Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SMAD1
NM_005900.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03
Variant links:
Genes affected
SMAD1 (HGNC:6767): (SMAD family member 1) The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15483886).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD1NM_005900.3 linkc.623C>T p.Thr208Ile missense_variant Exon 3 of 7 ENST00000302085.9 NP_005891.1 Q15797-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMAD1ENST00000302085.9 linkc.623C>T p.Thr208Ile missense_variant Exon 3 of 7 1 NM_005900.3 ENSP00000305769.4 Q15797-1
SMAD1ENST00000394092.6 linkc.623C>T p.Thr208Ile missense_variant Exon 3 of 7 1 ENSP00000377652.2 Q15797-1
SMAD1ENST00000515385.1 linkc.623C>T p.Thr208Ile missense_variant Exon 3 of 7 2 ENSP00000426568.1 Q15797-1
SMAD1ENST00000502342.1 linkn.*57C>T downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251278
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135808
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461820
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000831
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.623C>T (p.T208I) alteration is located in exon 3 (coding exon 2) of the SMAD1 gene. This alteration results from a C to T substitution at nucleotide position 623, causing the threonine (T) at amino acid position 208 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
21
DANN
Benign
0.94
DEOGEN2
Benign
0.40
T;T;T
Eigen
Benign
-0.17
Eigen_PC
Benign
0.053
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
.;.;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Benign
0.81
L;L;L
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.64
N;N;N
REVEL
Benign
0.22
Sift
Benign
0.63
T;T;T
Sift4G
Benign
0.49
T;T;T
Polyphen
0.0030
B;B;B
Vest4
0.26
MutPred
0.22
Loss of phosphorylation at T208 (P = 0.0041);Loss of phosphorylation at T208 (P = 0.0041);Loss of phosphorylation at T208 (P = 0.0041);
MVP
0.37
MPC
0.12
ClinPred
0.34
T
GERP RS
5.1
Varity_R
0.38
gMVP
0.34

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.

Other links and lift over

dbSNP: rs775020524; hg19: chr4-146461178; API