rs6743496

Variant names:

• chr2-190912589-A-G
• rs6743496
• NM_014905.5:c.1038+2268A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014905.5(GLS):​c.1038+2268A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,824 control chromosomes in the GnomAD database, including 19,284 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 0.47 (19284 hom., cov: 30)
• Consequence: GLS NM_014905.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577
• Publications: 3 publications found

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]

STAT1 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014905.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	NM_014905.5	MANE Select	c.1038+2268A>G		intron	N/A	NP_055720.3
	GLS	NM_001437282.1		c.1038+2268A>G		intron	N/A	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.1038+2268A>G		intron	N/A	NP_001243239.1	O94925-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.1038+2268A>G		intron	N/A	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.1038+2268A>G		intron	N/A	ENSP00000340689.4	O94925-3
	STAT1	ENST00000673816.1		c.2239-3589T>C		intron	N/A	ENSP00000501127.1	A0A669KB56

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70717 AN: 151706 Hom.: 19275 Cov.: 30

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.476

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.466 AC: 70759 AN: 151824 Hom.: 19284 Cov.: 30 AF XY: 0.468 AC XY: 34707 AN XY: 74214

African (AFR) AF: 0.210 AC: 8705 AN: 41416

American (AMR) AF: 0.416 AC: 6335 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1823 AN: 3466

East Asian (EAS) AF: 0.156 AC: 808 AN: 5178

South Asian (SAS) AF: 0.498 AC: 2392 AN: 4808

European-Finnish (FIN) AF: 0.669 AC: 7041 AN: 10526

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41964 AN: 67884

Other (OTH) AF: 0.474 AC: 998 AN: 2104

Alfa AF: 0.516 Hom.: 3199

Bravo AF: 0.436

Asia WGS AF: 0.358 AC: 1242 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.27
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6743496;

hg19: chr2-191777315;