rs190539169

Variant names:

• chr2-190932730-A-G
• rs190539169
• ENST00000338435.9:c.1665A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-190932730-A-G
• chr2-190932730-A-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001256310.2(GLS):​c.1665A>G​(p.Pro555Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,600,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: GLS NM_001256310.2 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.59
• Publications: 0 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: Illumina, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

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

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-190932730-A-G is Benign according to our data. Variant chr2-190932730-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3039095.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000257 (39/152008) while in subpopulation AFR AF = 0.000939 (39/41546). AF 95% confidence interval is 0.000705. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256310.2. 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.1650+1093A>G		intron	N/A	NP_055720.3
	GLS	NM_001256310.2		c.1665A>G	p.Pro555Pro	synonymous	Exon 15 of 15	NP_001243239.1	O94925-3
	GLS	NM_001437283.1		c.*44A>G		3_prime_UTR	Exon 15 of 15	NP_001424212.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000338435.9	TSL:1	c.1665A>G	p.Pro555Pro	synonymous	Exon 15 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.1650+1093A>G		intron	N/A	ENSP00000317379.3	O94925-1
	GLS	ENST00000409215.5	TSL:4	c.180A>G	p.Pro60Pro	synonymous	Exon 4 of 4	ENSP00000387135.1	B8ZZC5

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000606 AC: 14 AN: 231122 AF XY: 0.0000315

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000380 AC: 55 AN: 1448402 Hom.: 0 Cov.: 27 AF XY: 0.0000305 AC XY: 22 AN XY: 720458

African (AFR) AF: 0.00137 AC: 45 AN: 32950

American (AMR) AF: 0.00 AC: 0 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39188

South Asian (SAS) AF: 0.00 AC: 0 AN: 84226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1105310

Other (OTH) AF: 0.0000167 AC: 1 AN: 59880

GnomAD4 genome AF: 0.000257 AC: 39 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74336

African (AFR) AF: 0.000939 AC: 39 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67784

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000344

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GLS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.72
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs190539169; hg19: chr2-191797456;