chr5-170805849-G-C

Position:

• chr5-170805849-G-C

Variant summary

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

The NM_014211.3(GABRP):​c.675G>C​(p.Glu225Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRP NM_014211.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.746

Genes affected

GABRP (HGNC:4089): (gamma-aminobutyric acid type A receptor subunit pi) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

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	UniProt
GABRP	NM_014211.3	c.675G>C	p.Glu225Asp	missense_variant	7/10	ENST00000265294.9
GABRP	NM_001291985.2	c.675G>C	p.Glu225Asp	missense_variant	7/9
GABRP	XM_024446012.2	c.675G>C	p.Glu225Asp	missense_variant	7/10
GABRP	XM_005265872.2	c.438G>C	p.Glu146Asp	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRP	ENST00000265294.9	c.675G>C	p.Glu225Asp	missense_variant	7/10	1	NM_014211.3	P1
GABRP	ENST00000518525.5	c.675G>C	p.Glu225Asp	missense_variant	8/11	5		P1
GABRP	ENST00000519598.1	c.675G>C	p.Glu225Asp	missense_variant	7/10	5
GABRP	ENST00000519385.5	c.675G>C	p.Glu225Asp	missense_variant	7/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 18, 2021

The c.675G>C (p.E225D) alteration is located in exon 7 (coding exon 6) of the GABRP gene. This alteration results from a G to C substitution at nucleotide position 675, causing the glutamic acid (E) at amino acid position 225 to be replaced by an aspartic acid (D). 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	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;.
Eigen	Benign	0.024
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0090	D;D;T;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.62
MutPred		0.37		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.87
MPC		0.40
ClinPred		0.88	D
GERP RS		-0.92
Varity_R		0.28
gMVP		0.41

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: rs1487958867; hg19: chr5-170232853;