chr12-53382330-C-T

Variant summary

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

The NM_138473.3(SP1):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SP1
NM_138473.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12
Variant links:
Genes affected
SP1 (HGNC:11205): (Sp1 transcription factor) The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters. The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. Post-translational modifications such as phosphorylation, acetylation, glycosylation, and proteolytic processing significantly affect the activity of this protein, which can be an activator or a repressor. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2014]

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=0.07389018).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SP1NM_138473.3 linkc.383C>T p.Thr128Ile missense_variant Exon 3 of 6 ENST00000327443.9 NP_612482.2 P08047-1
SP1NM_003109.1 linkc.362C>T p.Thr121Ile missense_variant Exon 3 of 6 NP_003100.1 P08047-2
SP1NM_001251825.2 linkc.239C>T p.Thr80Ile missense_variant Exon 3 of 6 NP_001238754.1 P08047-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SP1ENST00000327443.9 linkc.383C>T p.Thr128Ile missense_variant Exon 3 of 6 1 NM_138473.3 ENSP00000329357.4 P08047-1
SP1ENST00000426431.2 linkc.362C>T p.Thr121Ile missense_variant Exon 3 of 6 1 ENSP00000404263.2 P08047-2
SP1ENST00000548560.1 linkc.362C>T p.Thr121Ile missense_variant Exon 2 of 2 2 ENSP00000458133.1 H3BVI2
SP1ENST00000551969.5 linkc.239C>T p.Thr80Ile missense_variant Exon 3 of 3 3 ENSP00000457804.1 H3BUU5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461882
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.383C>T (p.T128I) alteration is located in exon 3 (coding exon 3) of the SP1 gene. This alteration results from a C to T substitution at nucleotide position 383, causing the threonine (T) at amino acid position 128 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
0.21
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
21
DANN
Benign
0.90
DEOGEN2
Benign
0.25
T;T;.;.
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.76
T;T;T;T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.074
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.69
.;N;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.30
N;N;N;N
REVEL
Benign
0.023
Sift
Benign
0.092
T;T;T;T
Sift4G
Benign
0.11
T;T;T;T
Polyphen
0.013
.;B;.;.
Vest4
0.29, 0.28
MutPred
0.27
.;Gain of catalytic residue at T128 (P = 0.0047);.;.;
MVP
0.37
MPC
0.074
ClinPred
0.097
T
GERP RS
2.1
Varity_R
0.039
gMVP
0.31

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: rs775596739; hg19: chr12-53776114; COSMIC: COSV105235658; API