chr21-25758109-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_002040.4(GABPA):c.653C>T(p.Ser218Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,611,070 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: 0.000019 ( 0 hom. )
Consequence
GABPA
NM_002040.4 missense
NM_002040.4 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 4.58
Genes affected
GABPA (HGNC:4071): (GA binding protein transcription factor subunit alpha) This gene encodes one of three GA-binding protein transcription factor subunits which functions as a DNA-binding subunit. Since this subunit shares identity with a subunit encoding the nuclear respiratory factor 2 gene, it is likely involved in activation of cytochrome oxidase expression and nuclear control of mitochondrial function. This subunit also shares identity with a subunit constituting the transcription factor E4TF1, responsible for expression of the adenovirus E4 gene. Because of its chromosomal localization and ability to form heterodimers with other polypeptides, this gene may play a role in the Down Syndrome phenotype. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, GABPA
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3764428).
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABPA | NM_002040.4 | c.653C>T | p.Ser218Leu | missense_variant | 6/10 | ENST00000400075.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABPA | ENST00000400075.4 | c.653C>T | p.Ser218Leu | missense_variant | 6/10 | 1 | NM_002040.4 | P1 | |
GABPA | ENST00000354828.7 | c.653C>T | p.Ser218Leu | missense_variant | 6/10 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151978Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248692Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134544
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1458974Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 725834
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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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 submitter | clinical testing | Ambry Genetics | Jan 10, 2023 | The c.653C>T (p.S218L) alteration is located in exon 6 (coding exon 5) of the GABPA gene. This alteration results from a C to T substitution at nucleotide position 653, causing the serine (S) at amino acid position 218 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Loss of glycosylation at S218 (P = 0.0425);Loss of glycosylation at S218 (P = 0.0425);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at