NM_014905.5:c.36C>T

Variant names:

• chr2-190881120-C-T
• rs772006721
• NM_014905.5:c.36C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP7 BS1

The NM_014905.5(GLS):​c.36C>T​(p.Asp12Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,408,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GLS NM_014905.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 2 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]

GLS Gene-Disease associations (from GenCC):

• glutaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• global developmental delay, progressive ataxia, and elevated glutamine

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• developmental and epileptic encephalopathy, 71

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000228509 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000426 (6/1408802) while in subpopulation EAS AF = 0.0000549 (2/36412). AF 95% confidence interval is 0.0000091. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.36C>T	p.Asp12Asp	synonymous	Exon 1 of 18	NP_055720.3
	GLS	NM_001437282.1		c.36C>T	p.Asp12Asp	synonymous	Exon 1 of 17	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.36C>T	p.Asp12Asp	synonymous	Exon 1 of 15	NP_001243239.1	O94925-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.36C>T	p.Asp12Asp	synonymous	Exon 1 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.36C>T	p.Asp12Asp	synonymous	Exon 1 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000479552.1	TSL:1	n.249C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1408802 Hom.: 0 Cov.: 32 AF XY: 0.00000430 AC XY: 3 AN XY: 698264

African (AFR) AF: 0.00 AC: 0 AN: 32038

American (AMR) AF: 0.00 AC: 0 AN: 39206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.0000549 AC: 2 AN: 36412

South Asian (SAS) AF: 0.00 AC: 0 AN: 81310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1093920

Other (OTH) AF: 0.00 AC: 0 AN: 58574

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		-0.10
PromoterAI		-0.0018	Neutral
Mutation Taster		=100/0	polymorphism

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: rs772006721; hg19: chr2-191745846;