rs138173310

chr5-151822857-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000171.4(GLRA1):c.1166A>C(p.Asn389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.112

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010035008).
• BP6: Variant 5-151822857-T-G is Benign according to our data. Variant chr5-151822857-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577509.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000644 (98/152272) while in subpopulation AFR AF= 0.00214 (89/41552). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.1166A>C	p.Asn389Thr	missense_variant	9/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.1190A>C	p.Asn397Thr	missense_variant	9/9
GLRA1	NM_001292000.2	c.917A>C	p.Asn306Thr	missense_variant	8/8
GLRA1	XM_047417105.1	c.1214A>C	p.Asn405Thr	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.1166A>C	p.Asn389Thr	missense_variant	9/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.1190A>C	p.Asn397Thr	missense_variant	9/9	1		A1
GLRA1	ENST00000462581.6	c.*924A>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251336 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135838

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52 AN XY: 727204

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000537 AC XY: 40 AN XY: 74452

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000688

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary hyperekplexia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.0040
Dann	Benign	0.79
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.27
Sift	Benign	0.60	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;B
Vest4		0.15
MVP		0.59
MPC		0.050
ClinPred		0.0064	T
GERP RS		-3.4
Varity_R		0.046
gMVP		0.53

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

Other links and lift over

dbSNP: rs138173310; hg19: chr5-151202418;