NM_005271.5:c.1403-40_1403-39insTTTTAGCAATTTTTTGATCTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr10-87057821-G-GAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGATCAAAAAATTGCTAAAA
• rs35186250
• NM_005271.5:c.1403-40_1403-39insTTTTAGCAATTTTTTGATCTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_005271.5(GLUD1):​c.1403-40_1403-39insTTTTAGCAATTTTTTGATCTTTTTTTTTTTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000078 (0 hom., cov: 0)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism-hyperammonemia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.1403-40_1403-39insTTTTAGCAATTTTTTGATCTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron_variant	Intron 10 of 12	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.1403-40_1403-39insTTTTAGCAATTTTTTGATCTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron_variant	Intron 10 of 12	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes AF: 0.00000784 AC: 1 AN: 127608 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000784 AC: 1 AN: 127608 Hom.: 0 Cov.: 0 AF XY: 0.0000163 AC XY: 1 AN XY: 61312

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000276 AC: 1 AN: 36212

American (AMR) AF: 0.00 AC: 0 AN: 12992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3006

East Asian (EAS) AF: 0.00 AC: 0 AN: 4744

South Asian (SAS) AF: 0.00 AC: 0 AN: 3888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57172

Other (OTH) AF: 0.00 AC: 0 AN: 1692

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24

Splicing

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

Other links and lift over

dbSNP: rs35186250; hg19: chr10-88817578;