rs138173310

Variant names:

• chr5-151822857-T-C
• rs138173310
• NM_000171.4:c.1166A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-151822857-T-C
• chr5-151822857-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000171.4(GLRA1):​c.1166A>G​(p.Asn389Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N389T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.112
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 (MetaRNN=0.06768015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1166A>G	p.Asn389Ser	missense_variant	Exon 9 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1190A>G	p.Asn397Ser	missense_variant	Exon 9 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.917A>G	p.Asn306Ser	missense_variant	Exon 8 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.1214A>G	p.Asn405Ser	missense_variant	Exon 9 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1166A>G	p.Asn389Ser	missense_variant	Exon 9 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.1190A>G	p.Asn397Ser	missense_variant	Exon 9 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*924A>G		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*924A>G		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.0030
DANN	Benign	0.50
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	.;L
PhyloP100		0.11
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.28	N;N
REVEL	Benign	0.26
Sift	Benign	0.76	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.37		.;Gain of glycosylation at N397 (P = 0.0059);
MVP		0.54
MPC		0.042
ClinPred		0.057	T
GERP RS		-3.4
Varity_R		0.030
gMVP		0.45
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs138173310; hg19: chr5-151202418;