rs1546646

Positions:

• chr2-190963870-A-G
• chr2-190963870-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014905.5(GLS):​c.*884A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,958 control chromosomes in the GnomAD database, including 21,078 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (21076 hom., cov: 32)
  • Exomes 𝑓: 0.50 (2 hom.)
• Consequence: GLS NM_014905.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.575

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLS	NM_014905.5	c.*884A>G		3_prime_UTR_variant	18/18	ENST00000320717.8	NP_055720.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLS	ENST00000320717.8	c.*884A>G		3_prime_UTR_variant	18/18	1	NM_014905.5	ENSP00000317379	P1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76875 AN: 151826 Hom.: 21064 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.498

GnomAD4 exome AF: 0.500 AC: 7 AN: 14 Hom.: 2 Cov.: 0 AF XY: 0.500 AC XY: 3 AN XY: 6

Gnomad4 FIN exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.506 AC: 76912 AN: 151944 Hom.: 21076 Cov.: 32 AF XY: 0.506 AC XY: 37578 AN XY: 74256

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.519

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.498

Alfa AF: 0.541 Hom.: 6085

Bravo AF: 0.481

Asia WGS AF: 0.344 AC: 1197 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.41

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: rs1546646; hg19: chr2-191828596;