rs17096421

Positions:

• chr10-87060835-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005271.5(GLUD1):​c.1060-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,614,148 control chromosomes in the GnomAD database, including 2,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (122 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1897 hom.)
• Consequence: GLUD1 NM_005271.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.4035
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.931

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-87060835-A-T is Benign according to our data. Variant chr10-87060835-A-T is described in ClinVar as [Benign]. Clinvar id is 129162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLUD1	NM_005271.5	c.1060-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000277865.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLUD1	ENST00000277865.5	c.1060-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005271.5	P1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4762 AN: 152176 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0299 AC: 7521 AN: 251470 Hom.: 164 AF XY: 0.0296 AC XY: 4027 AN XY: 135914

Gnomad AFR exome AF: 0.00991

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0480

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0463 AC: 67662 AN: 1461854 Hom.: 1897 Cov.: 33 AF XY: 0.0447 AC XY: 32539 AN XY: 727230

Gnomad4 AFR exome AF: 0.00830

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.0547

Gnomad4 OTH exome AF: 0.0399

GnomAD4 genome AF: 0.0313 AC: 4764 AN: 152294 Hom.: 122 Cov.: 32 AF XY: 0.0300 AC XY: 2232 AN XY: 74472

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0336

Gnomad4 NFE AF: 0.0505

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0368 Hom.: 29

Bravo AF: 0.0295

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -

Hyperinsulinism-hyperammonemia syndrome Benign:2

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 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs17096421; hg19: chr10-88820592;