7-21429536-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003112.5(SP4):​c.371C>T​(p.Ser124Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,778 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SP4
NM_003112.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.17
Variant links:
Genes affected
SP4 (HGNC:11209): (Sp4 transcription factor) The protein encoded by this gene is a transcription factor that can bind to the GC promoter region of a variety of genes, including those of the photoreceptor signal transduction system. The encoded protein binds to the same sites in promoter CpG islands as does the transcription factor SP1, although its expression is much more restricted compared to that of SP1. This gene may be involved in bipolar disorder and schizophrenia. [provided by RefSeq, May 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13257661).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SP4NM_003112.5 linkuse as main transcriptc.371C>T p.Ser124Leu missense_variant 3/6 ENST00000222584.8 NP_003103.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SP4ENST00000222584.8 linkuse as main transcriptc.371C>T p.Ser124Leu missense_variant 3/61 NM_003112.5 ENSP00000222584 P1
SP4ENST00000649633.1 linkuse as main transcriptc.320C>T p.Ser107Leu missense_variant 3/6 ENSP00000496957
SP4ENST00000432066.2 linkuse as main transcriptc.7+1278C>T intron_variant 5 ENSP00000393623
SP4ENST00000448246.1 linkuse as main transcriptc.123+744C>T intron_variant, NMD_transcript_variant 5 ENSP00000390817

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251468
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461594
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727110
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 14, 2022The c.371C>T (p.S124L) alteration is located in exon 3 (coding exon 3) of the SP4 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the serine (S) at amino acid position 124 to be replaced by a leucine (L). 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
0.17
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-0.19
Eigen_PC
Benign
0.055
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.2
L;.
MutationTaster
Benign
0.98
D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.0
N;.
REVEL
Benign
0.061
Sift
Uncertain
0.0080
D;.
Sift4G
Benign
0.20
T;.
Polyphen
0.043
B;.
Vest4
0.33
MutPred
0.16
Loss of phosphorylation at S124 (P = 0.0012);.;
MVP
0.12
MPC
0.041
ClinPred
0.47
T
GERP RS
4.5
Varity_R
0.18
gMVP
0.16

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: rs374429537; hg19: chr7-21469154; COSMIC: COSV56025759; COSMIC: COSV56025759; API