chrX-14730234-T-C

Position:

• chrX-14730234-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002063.4(GLRA2):​c.1108T>C​(p.Phe370Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

Genes affected

GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA2	NM_002063.4	c.1108T>C	p.Phe370Leu	missense_variant	9/9	ENST00000218075.9	NP_002054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9	c.1108T>C	p.Phe370Leu	missense_variant	9/9	1	NM_002063.4	ENSP00000218075	A1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, X-linked, syndromic, Pilorge type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed missense variant c.1108T>C(p.Phe370Leu) in GLRA2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1108T>C variant is absent in gnomAD Exomes.The amino acid Phenyl alanine at position 370 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe370Leu in GLRA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.53	.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0010	.;B;B
Vest4		0.70
MutPred		0.35		.;Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);
MVP		0.87
MPC		1.3
ClinPred		0.63	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-14748356;