Genetic Variant GABRP:p.Pro39Ser (chr5-170789190-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014211.3(GABRP):c.115C>T(p.Pro39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GABRP
NM_014211.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.02

Variant links:

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]

GABRP links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GABRP	NM_014211.3 link	c.115C>T	p.Pro39Ser	missense_variant	Exon 3 of 10	ENST00000265294.9	NP_055026.1
GABRP	NM_001291985.2 link	c.115C>T	p.Pro39Ser	missense_variant	Exon 3 of 9		NP_001278914.1	O00591B4DTP4E7EWG0
GABRP	XM_024446012.2 link	c.115C>T	p.Pro39Ser	missense_variant	Exon 3 of 10		XP_024301780.1
GABRP	XM_005265872.2 link	c.-66+522C>T		intron_variant	Intron 1 of 7		XP_005265929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9 link	c.115C>T	p.Pro39Ser	missense_variant	Exon 3 of 10	1	NM_014211.3	ENSP00000265294.4		O00591

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251470

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

.;.;.;.;T;.;T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.46

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.074

MutationAssessor

Benign

0.55

.;.;.;.;N;.;N;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

D;D;D;D;N;D;N;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

D;D;D;T;D;D;D;D;D

Sift4G

Benign

0.16

T;T;D;T;T;D;T;T;T

Polyphen

0.99, 1.0

.;.;.;.;D;.;D;D;.

Vest4

0.45, 0.48, 0.43, 0.42

MutPred

0.37

Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);

MVP

0.94

MPC

0.29

ClinPred

0.91

GERP RS

5.1

Varity_R

0.20

gMVP

0.59

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over