10-87050580-T-TA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005271.5(GLUD1):c.*1170_*1171insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 136,270 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.018 (30 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GLUD1 NM_005271.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0177 (2409/136270) while in subpopulation AFR AF= 0.0391 (1452/37138). AF 95% confidence interval is 0.0374. There are 30 homozygotes in gnomad4. There are 1186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 2407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLUD1	NM_005271.5	c.*1170_*1171insT		3_prime_UTR_variant	13/13	ENST00000277865.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLUD1	ENST00000277865.5	c.*1170_*1171insT		3_prime_UTR_variant	13/13	1	NM_005271.5	P1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2407 AN: 136254 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00895

Gnomad EAS AF: 0.00378

Gnomad SAS AF: 0.00325

Gnomad FIN AF: 0.00742

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.0153

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0177 AC: 2409 AN: 136270 Hom.: 30 Cov.: 32 AF XY: 0.0180 AC XY: 1186 AN XY: 65916

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.00895

Gnomad4 EAS AF: 0.00379

Gnomad4 SAS AF: 0.00327

Gnomad4 FIN AF: 0.00742

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.0153

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperinsulinism, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs80258277; hg19: chr10-88810337;