2-190929215-G-A

Variant names:

• chr2-190929215-G-A
• rs13414554
• NM_014905.5:c.1426-1222G>A

Variant summary

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

The NM_014905.5(GLS):​c.1426-1222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 150,726 control chromosomes in the GnomAD database, including 3,898 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 0.22 (3898 hom., cov: 30)
• Consequence: GLS NM_014905.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.358
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	NM_014905.5	MANE Select	c.1426-1222G>A		intron	N/A	NP_055720.3
	GLS	NM_001437282.1		c.1426-1222G>A		intron	N/A	NP_001424211.1
	GLS	NM_001256310.2		c.1426-1222G>A		intron	N/A	NP_001243239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.1426-1222G>A		intron	N/A	ENSP00000317379.3
	GLS	ENST00000338435.9	TSL:1	c.1426-1222G>A		intron	N/A	ENSP00000340689.4
	STAT1	ENST00000673816.1		c.2239-20215C>T		intron	N/A	ENSP00000501127.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32733 AN: 150606 Hom.: 3900 Cov.: 30

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.206

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

GnomAD4 genome AF: 0.217 AC: 32732 AN: 150726 Hom.: 3898 Cov.: 30 AF XY: 0.215 AC XY: 15827 AN XY: 73600

African (AFR) AF: 0.152 AC: 6255 AN: 41174

American (AMR) AF: 0.167 AC: 2532 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 922 AN: 3458

East Asian (EAS) AF: 0.460 AC: 2356 AN: 5122

South Asian (SAS) AF: 0.176 AC: 842 AN: 4780

European-Finnish (FIN) AF: 0.242 AC: 2431 AN: 10056

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16658 AN: 67686

Other (OTH) AF: 0.211 AC: 441 AN: 2094

Alfa AF: 0.210 Hom.: 417

Bravo AF: 0.208

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.6
DANN	Benign	0.48
PhyloP100		0.36
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: rs13414554; hg19: chr2-191793941;