2-190905887-T-G

Variant names:

• chr2-190905887-T-G
• rs3771311
• NM_014905.5:c.979+720T>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.979+720T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,038 control chromosomes in the GnomAD database, including 1,907 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 0.14 (1907 hom., cov: 32)
• Consequence: GLS NM_014905.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.165
• Publications: 6 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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• developmental and epileptic encephalopathy, 71

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.296 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.979+720T>G		intron	N/A	NP_055720.3
	GLS	NM_001437282.1		c.979+720T>G		intron	N/A	NP_001424211.1
	GLS	NM_001256310.2		c.979+720T>G		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.979+720T>G		intron	N/A	ENSP00000317379.3
	GLS	ENST00000338435.9	TSL:1	c.979+720T>G		intron	N/A	ENSP00000340689.4
	GLS	ENST00000412247.2	TSL:3	c.979+720T>G		intron	N/A	ENSP00000403329.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20698 AN: 151920 Hom.: 1898 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0987

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.136 AC: 20729 AN: 152038 Hom.: 1907 Cov.: 32 AF XY: 0.139 AC XY: 10311 AN XY: 74294

African (AFR) AF: 0.129 AC: 5372 AN: 41486

American (AMR) AF: 0.303 AC: 4632 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 529 AN: 3468

East Asian (EAS) AF: 0.224 AC: 1157 AN: 5170

South Asian (SAS) AF: 0.298 AC: 1439 AN: 4828

European-Finnish (FIN) AF: 0.0464 AC: 491 AN: 10590

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.0987 AC: 6703 AN: 67924

Other (OTH) AF: 0.143 AC: 301 AN: 2104

Alfa AF: 0.110 Hom.: 749

Bravo AF: 0.157

Asia WGS AF: 0.233 AC: 811 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.17
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: rs3771311; hg19: chr2-191770613;