Genetic Variant GABRR1:c.123-5G>T (chr6-89203490-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001256704.1(GABRR1):c.-142-2G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GABRR1
NM_001256704.1 splice_acceptor, intron

Scores

Splicing: ADA: 0.00005073

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

13 publications found

Variant links:

Genes affected

GABRR1 (HGNC:4090): (gamma-aminobutyric acid type A receptor subunit rho1) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA receptors, which are ligand-gated chloride channels. GABRR1 is a member of the rho subunit family. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GABRR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.045801528 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 3, new splice context is: atttttaatgttcattgtAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256704.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GABRR1	NM_002042.5	MANE Select	c.123-5G>T	splice_region intron	N/A	NP_002033.2	P24046-1
GABRR1	NM_001256703.1		c.123-2225G>T	intron	N/A	NP_001243632.1	P24046-2
GABRR1	NM_001256704.1		c.-142-2G>T	splice_acceptor intron	N/A	NP_001243633.1	P24046-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GABRR1	ENST00000454853.7	TSL:1 MANE Select	c.123-5G>T	splice_region intron	N/A	ENSP00000412673.2	P24046-1
GABRR1	ENST00000435811.5	TSL:2	c.123-2225G>T	intron	N/A	ENSP00000394687.1	P24046-2
GABRR1	ENST00000369451.7	TSL:5	c.-139-5G>T	splice_region intron	N/A	ENSP00000358463.3	P24046-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251096

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.87e-7

AC:

AN:

1455606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106318

Other (OTH)

AF:

0.00

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000246

Hom.:

90770

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.0

(source)

DANN

Benign

0.60

PhyloP100

1.2

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000051

dbscSNV1_RF

Benign

0.036

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over