rs883844

Variant names:

• chr2-190961043-T-C
• rs883844
• NM_014905.5:c.1854-1787T>C

Variant summary

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

The NM_014905.5(GLS):​c.1854-1787T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 152,004 control chromosomes in the GnomAD database, including 28,456 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 0.61 (28456 hom., cov: 32)
• Consequence: GLS NM_014905.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 12 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, Labcorp Genetics (formerly Invitae), Illumina, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLS	NM_014905.5	c.1854-1787T>C		intron_variant	Intron 17 of 17	ENST00000320717.8	NP_055720.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLS	ENST00000320717.8	c.1854-1787T>C		intron_variant	Intron 17 of 17	1	NM_014905.5	ENSP00000317379.3

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91870 AN: 151886 Hom.: 28411 Cov.: 32

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.605 AC: 91963 AN: 152004 Hom.: 28456 Cov.: 32 AF XY: 0.608 AC XY: 45163 AN XY: 74286

African (AFR) AF: 0.518 AC: 21443 AN: 41396

American (AMR) AF: 0.676 AC: 10339 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1892 AN: 3466

East Asian (EAS) AF: 0.351 AC: 1817 AN: 5172

South Asian (SAS) AF: 0.605 AC: 2915 AN: 4818

European-Finnish (FIN) AF: 0.694 AC: 7328 AN: 10562

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44235 AN: 67994

Other (OTH) AF: 0.592 AC: 1247 AN: 2108

Alfa AF: 0.635 Hom.: 50567

Bravo AF: 0.602

Asia WGS AF: 0.496 AC: 1727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.78
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs883844; hg19: chr2-191825769;