2-190927384-A-G

Variant names:

• chr2-190927384-A-G
• rs1373946574
• NM_014905.5:c.1327A>G

Variant summary

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

The NM_014905.5(GLS):​c.1327A>G​(p.Thr443Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GLS NM_014905.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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]

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

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 rank	MANE	Protein	UniProt
GLS	NM_014905.5	c.1327A>G	p.Thr443Ala	missense_variant	Exon 12 of 18	ENST00000320717.8	NP_055720.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLS	ENST00000320717.8	c.1327A>G	p.Thr443Ala	missense_variant	Exon 12 of 18	1	NM_014905.5	ENSP00000317379.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Inborn genetic diseases Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1327A>G (p.T443A) alteration is located in exon 12 (coding exon 12) of the GLS gene. This alteration results from a A to G substitution at nucleotide position 1327, causing the threonine (T) at amino acid position 443 to be replaced by an alanine (A). 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	Pathogenic	0.83
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.5	H;H;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.57	P;P;.;.
Vest4		0.50
MutPred		0.51		Loss of phosphorylation at T443 (P = 0.038);Loss of phosphorylation at T443 (P = 0.038);.;.;
MVP		0.69
MPC		2.6
ClinPred		0.99	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.90

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: rs1373946574; hg19: chr2-191792110;