rs73285947

Variant names:

• chr5-151856293-A-C
• rs73285947
• NM_000171.4:c.559+8T>G

Your query was ambiguous. Multiple possible variants found:

• chr5-151856293-A-C
• chr5-151856293-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000171.4(GLRA1):​c.559+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,593,668 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (88 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (77 hom.)
• Consequence: GLRA1 NM_000171.4 splice_region, intron
• Scores: Splicing: ADA: 0.000009675
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0180
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-151856293-A-C is Benign according to our data. Variant chr5-151856293-A-C is described in ClinVar as Benign. ClinVar VariationId is 352315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.559+8T>G		splice_region intron	N/A	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.559+8T>G		splice_region intron	N/A	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.310+8T>G		splice_region intron	N/A	NP_001278929.1	Q14C71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.559+8T>G		splice_region intron	N/A	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.559+8T>G		splice_region intron	N/A	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.*317+8T>G		splice_region intron	N/A	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2623 AN: 152124 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00422 AC: 1061 AN: 251428 AF XY: 0.00305

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00171 AC: 2472 AN: 1441426 Hom.: 77 Cov.: 27 AF XY: 0.00148 AC XY: 1060 AN XY: 718410

African (AFR) AF: 0.0613 AC: 2020 AN: 32968

American (AMR) AF: 0.00316 AC: 141 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.000245 AC: 21 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5732

European-Non Finnish (NFE) AF: 0.0000329 AC: 36 AN: 1094010

Other (OTH) AF: 0.00408 AC: 243 AN: 59584

GnomAD4 genome AF: 0.0173 AC: 2632 AN: 152242 Hom.: 88 Cov.: 33 AF XY: 0.0162 AC XY: 1208 AN XY: 74444

African (AFR) AF: 0.0591 AC: 2455 AN: 41518

American (AMR) AF: 0.00876 AC: 134 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.0176 AC: 37 AN: 2108

Alfa AF: 0.00907 Hom.: 18

Bravo AF: 0.0198

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	GLRA1-related disorder (1)
-	-	1	Hereditary hyperekplexia (1)
-	-	1	Hyperekplexia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.65
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000097
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73285947; hg19: chr5-151235854;