2-173910024-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003111.5(SP3):​c.2263G>A​(p.Ala755Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SP3
NM_003111.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.64
Variant links:
Genes affected
SP3 (HGNC:11208): (Sp3 transcription factor) This gene belongs to a family of Sp1 related genes that encode transcription factors that regulate transcription by binding to consensus GC- and GT-box regulatory elements in target genes. This protein contains a zinc finger DNA-binding domain and several transactivation domains, and has been reported to function as a bifunctional transcription factor that either stimulates or represses the transcription of numerous genes. Transcript variants encoding different isoforms have been described for this gene, and one has been reported to initiate translation from a non-AUG (AUA) start codon. Additional isoforms, resulting from the use of alternate downstream translation initiation sites, have also been noted. A related pseudogene has been identified on chromosome 13. [provided by RefSeq, Feb 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.055858493).
BP6
Variant 2-173910024-C-T is Benign according to our data. Variant chr2-173910024-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2400883.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SP3NM_003111.5 linkc.2263G>A p.Ala755Thr missense_variant Exon 7 of 7 ENST00000310015.12 NP_003102.1 Q02447-1Q86TP0
SP3NM_001172712.1 linkc.2254G>A p.Ala752Thr missense_variant Exon 7 of 7 NP_001166183.1 Q02447Q59FX5B7ZLN9
SP3NM_001017371.5 linkc.2059G>A p.Ala687Thr missense_variant Exon 5 of 5 NP_001017371.3 Q02447-5Q59FX5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SP3ENST00000310015.12 linkc.2263G>A p.Ala755Thr missense_variant Exon 7 of 7 1 NM_003111.5 ENSP00000310301.6 Q02447-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000798
AC:
2
AN:
250526
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135382
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1461436
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727002
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Aug 30, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
22
DANN
Benign
0.59
DEOGEN2
Benign
0.044
T;T;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.056
T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
-0.81
N;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.15
N;N;.
REVEL
Benign
0.039
Sift
Benign
0.35
T;T;.
Sift4G
Benign
0.45
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.019
MutPred
0.27
Gain of glycosylation at A755 (P = 0.0054);.;.;
MVP
0.17
MPC
0.063
ClinPred
0.048
T
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.019
gMVP
0.33

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: rs758298021; hg19: chr2-174774752; COSMIC: COSV59467539; API