2-190963960-A-G

Variant names:

• chr2-190963960-A-G
• rs10437
• NM_014905.5:c.*974A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014905.5(GLS):​c.*974A>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 0.0864 in 152,130 control chromosomes in the GnomAD database, including 1,082 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 0.086 (1082 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GLS NM_014905.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.870

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLS	NM_014905.5	c.*974A>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000320717.8	NP_055720.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLS	ENST00000320717.8	c.*974A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_014905.5	ENSP00000317379.3

Frequencies

GnomAD3 genomes AF: 0.0862 AC: 13102 AN: 152012 Hom.: 1067 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0830

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0864 AC: 13137 AN: 152130 Hom.: 1082 Cov.: 32 AF XY: 0.0901 AC XY: 6698 AN XY: 74380

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0318

Gnomad4 OTH AF: 0.0821

Alfa AF: 0.0542 Hom.: 1141

Bravo AF: 0.107

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.88

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: rs10437; hg19: chr2-191828686;