5-170795407-C-T

Position:

chr5-170795407-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014211.3(GABRP):c.440C>T(p.Thr147Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GABRP
NM_014211.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GABRP	NM_014211.3 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	5/10	ENST00000265294.9	NP_055026.1
GABRP	NM_001291985.2 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	5/9		NP_001278914.1
GABRP	XM_024446012.2 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	5/10		XP_024301780.1
GABRP	XM_005265872.2 linkuse as main transcript	c.203C>T	p.Thr68Met	missense_variant	3/8		XP_005265929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	5/10	1	NM_014211.3	ENSP00000265294	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251380

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Aug 17, 2021

The c.440C>T (p.T147M) alteration is located in exon 5 (coding exon 4) of the GABRP gene. This alteration results from a C to T substitution at nucleotide position 440, causing the threonine (T) at amino acid position 147 to be replaced by a methionine (M). 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

0.31

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;.;D;D;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

2.9

.;.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.022

D;D;D;D;D;D

Sift4G

Uncertain

0.037

D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;D;.

Vest4

0.81, 0.81, 0.84

MutPred

0.59

Loss of catalytic residue at T147 (P = 0.0508);Loss of catalytic residue at T147 (P = 0.0508);Loss of catalytic residue at T147 (P = 0.0508);Loss of catalytic residue at T147 (P = 0.0508);Loss of catalytic residue at T147 (P = 0.0508);Loss of catalytic residue at T147 (P = 0.0508);

MVP

0.94

MPC

0.58

ClinPred

0.87

GERP RS

5.6

Varity_R

0.23

gMVP

0.55

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over