Genetic Variant GLRA1:c.559+8T>C (chr5-151856293-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000171.4(GLRA1):c.559+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 splice_region, intron

Scores

Splicing: ADA: 0.000009675

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Publications

0 publications found

Variant links:

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 Gene-Disease associations (from GenCC):

hyperekplexia 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GLRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GLRA1	NM_000171.4 link	c.559+8T>C	splice_region_variant, intron_variant	Intron 5 of 8	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2 link	c.559+8T>C	splice_region_variant, intron_variant	Intron 5 of 8		NP_001139512.1
GLRA1	NM_001292000.2 link	c.310+8T>C	splice_region_variant, intron_variant	Intron 4 of 7		NP_001278929.1
GLRA1	XM_047417105.1 link	c.607+8T>C	splice_region_variant, intron_variant	Intron 5 of 8		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GLRA1	ENST00000274576.9 link	c.559+8T>C	splice_region_variant, intron_variant	Intron 5 of 8	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2 link	c.559+8T>C	splice_region_variant, intron_variant	Intron 5 of 8	1		ENSP00000411593.2
GLRA1	ENST00000462581.6 link	n.*317+8T>C	splice_region_variant, intron_variant	Intron 4 of 7	1		ENSP00000430595.1
GLRA1	ENST00000471351.2 link	n.842+8T>C	splice_region_variant, intron_variant	Intron 5 of 7	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441462

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33000

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094010

Other (OTH)

AF:

0.0000168

AC:

AN:

59588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.0

(source)

DANN

Benign

0.67

PhyloP100

-0.018

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000097

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over