Genetic Variant GLUD1:p.Gly35Val (chr10-87094666-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005271.5(GLUD1):c.104G>T(p.Gly35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,090 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GLUD1
NM_005271.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0400

Publications

0 publications found

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:

SHLD2 (HGNC:28773): (shieldin complex subunit 2) Involved in negative regulation of double-strand break repair via homologous recombination; positive regulation of double-strand break repair via nonhomologous end joining; and positive regulation of isotype switching. Located in nucleus and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

SHLD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25630102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5 link	c.104G>T	p.Gly35Val	missense_variant	Exon 1 of 13	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5 link	c.104G>T	p.Gly35Val	missense_variant	Exon 1 of 13	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31958

American (AMR)

AF:

0.00

AC:

AN:

38654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24722

East Asian (EAS)

AF:

0.00

AC:

AN:

37580

South Asian (SAS)

AF:

0.00

AC:

AN:

81958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4058

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1087806

Other (OTH)

AF:

0.00

AC:

AN:

58212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.22

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.26

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.0

PhyloP100

-0.040

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.83

REVEL

Uncertain

0.58

Sift

Benign

0.49

Sift4G

Benign

0.18

Polyphen

0.030

Vest4

0.39

MutPred

0.26

Loss of helix (P = 0.0167);

MVP

0.90

MPC

1.4

ClinPred

0.076

GERP RS

2.7

PromoterAI

-0.068

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.055

gMVP

0.57

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over