NM_000171.4:c.1179C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000171.4(GLRA1):​c.1179C>A​(p.Pro393Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P393P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.42

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 5-151822844-G-T is Benign according to our data. Variant chr5-151822844-G-T is described in CliVar as Likely_benign. Clinvar id is 1618571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151822844-G-T is described in CliVar as Likely_benign. Clinvar id is 1618571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151822844-G-T is described in CliVar as Likely_benign. Clinvar id is 1618571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151822844-G-T is described in CliVar as Likely_benign. Clinvar id is 1618571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151822844-G-T is described in CliVar as Likely_benign. Clinvar id is 1618571.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GLRA1NM_000171.4 linkc.1179C>A p.Pro393Pro synonymous_variant Exon 9 of 9 ENST00000274576.9 NP_000162.2 P23415-2
GLRA1NM_001146040.2 linkc.1203C>A p.Pro401Pro synonymous_variant Exon 9 of 9 NP_001139512.1 P23415-1
GLRA1NM_001292000.2 linkc.930C>A p.Pro310Pro synonymous_variant Exon 8 of 8 NP_001278929.1 Q14C71
GLRA1XM_047417105.1 linkc.1227C>A p.Pro409Pro synonymous_variant Exon 9 of 9 XP_047273061.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GLRA1ENST00000274576.9 linkc.1179C>A p.Pro393Pro synonymous_variant Exon 9 of 9 1 NM_000171.4 ENSP00000274576.5 P23415-2
GLRA1ENST00000455880.2 linkc.1203C>A p.Pro401Pro synonymous_variant Exon 9 of 9 1 ENSP00000411593.2 P23415-1
GLRA1ENST00000462581.6 linkn.*937C>A non_coding_transcript_exon_variant Exon 8 of 8 1 ENSP00000430595.1 E5RJ70
GLRA1ENST00000462581.6 linkn.*937C>A 3_prime_UTR_variant Exon 8 of 8 1 ENSP00000430595.1 E5RJ70

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251416
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461852
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727228
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111986
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41424
American (AMR)
AF:
0.0000654
AC:
1
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary hyperekplexia Benign:1
Mar 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.070
DANN
Benign
0.45
PhyloP100
-5.4

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

Other links and lift over

dbSNP: rs772443569; hg19: chr5-151202405; API