chr2-190931645-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014905.5(GLS):c.1650+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,350,052 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 30 hom. )

Consequence

GLS
NM_014905.5 splice_region, intron

Scores

Splicing: ADA: 0.0003983

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.994

Variant links:

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 links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 2-190931645-A-C is Benign according to our data. Variant chr2-190931645-A-C is described in ClinVar as [Benign]. Clinvar id is 3050373.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000697 (106/152170) while in subpopulation SAS AF = 0.0218 (105/4824). AF 95% confidence interval is 0.0184. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLS	NM_014905.5 link	c.1650+8A>C		splice_region_variant, intron_variant	Intron 14 of 17	ENST00000320717.8	NP_055720.3	O94925-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLS	ENST00000320717.8 link	c.1650+8A>C		splice_region_variant, intron_variant	Intron 14 of 17	1	NM_014905.5	ENSP00000317379.3		O94925-1

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.00285

AC:

656

AN:

230320

AF XY:

0.00391

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000187

Gnomad OTH exome

AF:

0.000911

GnomAD4 exome

AF:

0.00139

AC:

1665

AN:

1197882

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

1234

AN XY:

607632

show subpopulations

Gnomad4 AFR exome

AF:

0.0000363

AC:

AN:

27566

Gnomad4 AMR exome

AF:

0.0000247

AC:

AN:

40416

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

23842

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

38050

Gnomad4 SAS exome

AF:

0.0207

AC:

1579

AN:

76256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52658

Gnomad4 NFE exome

AF:

0.0000181

AC:

AN:

884114

Gnomad4 Remaining exome

AF:

0.00130

AC:

AN:

50900

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000697

AC:

106

AN:

152170

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.0218

AC:

0.0217662

AN:

0.0217662

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000476

AC:

0.000475737

AN:

0.000475737

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000513

Hom.:

Bravo

AF:

0.000155

Asia WGS

AF:

0.0110

AC:

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GLS-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.71

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00040

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over