12-56475108-A-T

Position:

• chr12-56475108-A-T

Variant summary

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

The NM_013267.4(GLS2):​c.932T>A​(p.Phe311Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLS2 NM_013267.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

Genes affected

GLS2 (HGNC:29570): (glutaminase 2) The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

SPRYD4 (HGNC:27468): (SPRY domain containing 4) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285528 (HGNC:):

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
GLS2	NM_013267.4	c.932T>A	p.Phe311Tyr	missense_variant, splice_region_variant	10/18	ENST00000311966.9	NP_037399.2
SPRYD4	NM_207344.4	c.*5531A>T		3_prime_UTR_variant	2/2	ENST00000338146.7	NP_997227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLS2	ENST00000311966.9	c.932T>A	p.Phe311Tyr	missense_variant, splice_region_variant	10/18	1	NM_013267.4	ENSP00000310447.4
SPRYD4	ENST00000338146.7	c.*5531A>T		3_prime_UTR_variant	2/2	1	NM_207344.4	ENSP00000338034.5
ENSG00000285528	ENST00000648304.1	n.182+12829T>A		intron_variant				ENSP00000497190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2024

The c.932T>A (p.F311Y) alteration is located in exon 10 (coding exon 10) of the GLS2 gene. This alteration results from a T to A substitution at nucleotide position 932, causing the phenylalanine (F) at amino acid position 311 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.82	.;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	.;.;N
REVEL	Benign	0.27
Sift	Benign	0.084	.;.;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.38	.;.;B
Vest4		0.80
MutPred		0.60		.;.;Gain of catalytic residue at S307 (P = 0.0017);
MVP		0.63
MPC		1.2
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr12-56868892;