2-190953597-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014905.5(GLS):c.1683A>C(p.Ala561=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,611,020 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (84 hom.)
• Consequence: GLS NM_014905.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.60

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-190953597-A-C is Benign according to our data. Variant chr2-190953597-A-C is described in ClinVar as [Benign]. Clinvar id is 720765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00575 (876/152306) while in subpopulation EAS AF= 0.053 (275/5190). AF 95% confidence interval is 0.0478. There are 22 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLS	NM_014905.5	c.1683A>C	p.Ala561=	synonymous_variant	15/18	ENST00000320717.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLS	ENST00000320717.8	c.1683A>C	p.Ala561=	synonymous_variant	15/18	1	NM_014905.5	P1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152188 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00911 AC: 2287 AN: 251178 Hom.: 45 AF XY: 0.00808 AC XY: 1097 AN XY: 135740

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0567

Gnomad SAS exome AF: 0.00738

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00288 AC: 4195 AN: 1458714 Hom.: 84 Cov.: 28 AF XY: 0.00290 AC XY: 2102 AN XY: 725852

Gnomad4 AFR exome AF: 0.000868

Gnomad4 AMR exome AF: 0.0248

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0514

Gnomad4 SAS exome AF: 0.00707

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000938

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152306 Hom.: 22 Cov.: 32 AF XY: 0.00709 AC XY: 528 AN XY: 74480

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.0312

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0530

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00100 Hom.: 5

Bravo AF: 0.00663

Asia WGS AF: 0.0410 AC: 141 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GLS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.13
Dann	Benign	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

LitVar

Other links and lift over

dbSNP: rs3732211; hg19: chr2-191818323; COSMIC: COSV57844772;