rs2829900

Positions:

• chr21-25764684-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002040.4(GABPA):​c.1033G>A​(p.Glu345Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABPA NM_002040.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABPA	NM_002040.4	c.1033G>A	p.Glu345Lys	missense_variant	9/10	ENST00000400075.4	NP_002031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABPA	ENST00000400075.4	c.1033G>A	p.Glu345Lys	missense_variant	9/10	1	NM_002040.4	ENSP00000382948.3
GABPA	ENST00000354828.7	c.1033G>A	p.Glu345Lys	missense_variant	9/10	1		ENSP00000346886.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.17
Sift	Benign	0.066	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.85	P;P
Vest4		0.45
MutPred		0.20		Gain of ubiquitination at E345 (P = 0.0138);Gain of ubiquitination at E345 (P = 0.0138);
MVP		0.53
MPC		1.4
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.86

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

Other links and lift over

dbSNP: rs2829900; hg19: chr21-27136995;