2-190881301-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014905.5(GLS):c.217T>C(p.Ser73Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S73F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: GLS NM_014905.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

Genes affected

GLS (HGNC:4331): (glutaminase) This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30132288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLS	NM_014905.5	c.217T>C	p.Ser73Pro	missense_variant	1/18	ENST00000320717.8
LOC124906110	XR_007087791.1	n.344A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLS	ENST00000320717.8	c.217T>C	p.Ser73Pro	missense_variant	1/18	1	NM_014905.5	P1
	ENST00000413911.1	n.415A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 658756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.50e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

GLS: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.077	T;.
Eigen	Benign	0.0052
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.050
Sift	Benign	0.14	T;T
Sift4G	Benign	0.063	T;T
Polyphen		0.91	P;P
Vest4		0.23
MutPred		0.21		Loss of phosphorylation at S73 (P = 0.011);Loss of phosphorylation at S73 (P = 0.011);
MVP		0.56
MPC		0.61
ClinPred		0.60	D
GERP RS		3.6
Varity_R		0.29
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-191746027;