rs9421572

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005271.5(GLUD1):c.942A>G(p.Leu314=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,134 control chromosomes in the GnomAD database, including 14,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 1509 hom., cov: 32)

Exomes 𝑓: 0.11 ( 13415 hom. )

Consequence

GLUD1
NM_005271.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.168

Variant links:

Genes affected

GLUD1 (HGNC:4335): (glutamate dehydrogenase 1) This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X. [provided by RefSeq, Jan 2016]

GLUD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 10-87061032-T-C is Benign according to our data. Variant chr10-87061032-T-C is described in ClinVar as [Benign]. Clinvar id is 129164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.168 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLUD1	NM_005271.5 linkuse as main transcript	c.942A>G	p.Leu314=	synonymous_variant	7/13	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5 linkuse as main transcript	c.942A>G	p.Leu314=	synonymous_variant	7/13	1	NM_005271.5	ENSP00000277865	P1	P00367-1

Frequencies

GnomAD3 genomes

AF:

0.0938

AC:

14264

AN:

152078

Hom.:

1510

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0197

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0948

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.590

Gnomad SAS

AF:

0.0807

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0928

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.124

AC:

31252

AN:

251474

Hom.:

4207

AF XY:

0.122

AC XY:

16649

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.0712

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.589

Gnomad SAS exome

AF:

0.0712

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.0922

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.105

AC:

153756

AN:

1460938

Hom.:

13415

Cov.:

AF XY:

0.104

AC XY:

75703

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.0164

Gnomad4 AMR exome

AF:

0.0761

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.592

Gnomad4 SAS exome

AF:

0.0664

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.0919

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.0938

AC:

14272

AN:

152196

Hom.:

1509

Cov.:

AF XY:

0.0983

AC XY:

7317

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0196

Gnomad4 AMR

AF:

0.0949

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.590

Gnomad4 SAS

AF:

0.0812

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.0928

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.0844

Hom.:

300

Bravo

AF:

0.0905

Asia WGS

AF:

0.290

AC:

1005

AN:

3478

EpiCase

AF:

0.0870

EpiControl

AF:

0.0904

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hyperinsulinism-hyperammonemia syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.5

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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