rs1546646

Variant names:

• chr2-190963870-A-G
• rs1546646
• NM_014905.5:c.*884A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 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.*884A>G		3_prime_UTR	Exon 18 of 18	NP_055720.3
	GLS	NM_001437282.1		c.*844A>G		3_prime_UTR	Exon 17 of 17	NP_001424211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.*884A>G		3_prime_UTR	Exon 18 of 18	ENSP00000317379.3
	GLS	ENST00000417154.6	TSL:3	n.*2050A>G		non_coding_transcript_exon	Exon 18 of 18	ENSP00000388990.2
	GLS	ENST00000706565.1		n.*2247A>G		non_coding_transcript_exon	Exon 16 of 16	ENSP00000516450.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 6 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.359 AC: 14885 AN: 41448

American (AMR) AF: 0.417 AC: 6362 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1800 AN: 3468

East Asian (EAS) AF: 0.140 AC: 725 AN: 5186

South Asian (SAS) AF: 0.481 AC: 2317 AN: 4822

European-Finnish (FIN) AF: 0.670 AC: 7052 AN: 10524

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42022 AN: 67940

Other (OTH) AF: 0.498 AC: 1048 AN: 2106

Alfa AF: 0.538 Hom.: 6139

Bravo AF: 0.481

Asia WGS AF: 0.344 AC: 1197 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		0.57
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: rs1546646; hg19: chr2-191828596;