10-87057743-T-C

Position:

• chr10-87057743-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005271.5(GLUD1):​c.1442A>G​(p.His481Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,446,150 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: 0.0000021 (0 hom.)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23636088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.1442A>G	p.His481Arg	missense_variant	11/13	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.1442A>G	p.His481Arg	missense_variant	11/13	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446150 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.61	T
Sift4G	Benign	0.68	T
Polyphen		0.017	B
Vest4		0.32
MutPred		0.43		Gain of helix (P = 0.027);
MVP		0.96
MPC		1.4
ClinPred		0.40	T
GERP RS		5.0
Varity_R		0.40
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs1169592069; hg19: chr10-88817500;