chr10-87094394-C-A

Variant names:

• chr10-87094394-C-A
• NM_005271.5:c.376G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005271.5(GLUD1):​c.376G>T​(p.Asp126Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.376G>T	p.Asp126Tyr	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	c.376G>T	p.Asp126Tyr	missense_variant	Exon 1 of 13	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461078 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726854

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.65		Loss of sheet (P = 0.0817);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.89
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-88854151;