21-25764278-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_002040.4(GABPA):c.871G>A(p.Ala291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A291V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABPA NM_002040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABPA
• BP4: Computational evidence support a benign effect (MetaRNN=0.049945652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABPA	NM_002040.4	c.871G>A	p.Ala291Thr	missense_variant	8/10	ENST00000400075.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABPA	ENST00000400075.4	c.871G>A	p.Ala291Thr	missense_variant	8/10	1	NM_002040.4	P1
GABPA	ENST00000354828.7	c.871G>A	p.Ala291Thr	missense_variant	8/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.871G>A (p.A291T) alteration is located in exon 8 (coding exon 7) of the GABPA gene. This alteration results from a G to A substitution at nucleotide position 871, causing the alanine (A) at amino acid position 291 to be replaced by a threonine (T). 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	0.063
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Benign	0.85
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	0.63	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.049
Sift	Benign	0.61	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0	B;B
Vest4		0.068
MutPred		0.27		Gain of glycosylation at A291 (P = 0.0316);Gain of glycosylation at A291 (P = 0.0316);
MVP		0.24
MPC		1.2
ClinPred		0.85	D
GERP RS		2.8
Varity_R		0.024
gMVP		0.32

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: rs1005411702; hg19: chr21-27136589;