chr2-190964627-C-G

Variant names:

• chr2-190964627-C-G
• rs13035504
• NM_014905.5:c.*1641C>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.*1641C>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 0.12 in 152,146 control chromosomes in the GnomAD database, including 1,241 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 0.12 (1240 hom., cov: 32)
  • Exomes 𝑓: 0.29 (1 hom.)
• Consequence: GLS NM_014905.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.767
• 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: 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 -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 = 0.148 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.*1641C>G		3_prime_UTR	Exon 18 of 18	NP_055720.3
	GLS	NM_001437282.1		c.*1601C>G		3_prime_UTR	Exon 17 of 17	NP_001424211.1	H7C201

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.*1641C>G		3_prime_UTR	Exon 18 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000950145.1		c.*1641C>G		3_prime_UTR	Exon 19 of 19	ENSP00000620204.1
	GLS	ENST00000950146.1		c.*1641C>G		3_prime_UTR	Exon 16 of 16	ENSP00000620205.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18167 AN: 152004 Hom.: 1238 Cov.: 32

Gnomad AFR AF: 0.0679

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.292 AC: 7 AN: 24 Hom.: 1 Cov.: 0 AF XY: 0.333 AC XY: 6 AN XY: 18

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.333 AC: 6 AN: 18

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00160812), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.120 AC: 18194 AN: 152122 Hom.: 1240 Cov.: 32 AF XY: 0.118 AC XY: 8758 AN XY: 74370

African (AFR) AF: 0.0683 AC: 2833 AN: 41504

American (AMR) AF: 0.124 AC: 1899 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3472

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5174

South Asian (SAS) AF: 0.138 AC: 665 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10592

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10218 AN: 67978

Other (OTH) AF: 0.139 AC: 292 AN: 2108

Alfa AF: 0.0487 Hom.: 54

Bravo AF: 0.122

Asia WGS AF: 0.0980 AC: 344 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.26
DANN	Benign	0.42
PhyloP100		-0.77
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: rs13035504; hg19: chr2-191829353;