NM_005271.5:c.1403-43_1403-40delTTTT

Variant names:

• chr10-87057821-GAAAA-G
• rs35186250
• NM_005271.5:c.1403-43_1403-40delTTTT

Variant summary

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

The NM_005271.5(GLUD1):​c.1403-43_1403-40delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 721,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	NM_005271.5	MANE Select	c.1403-43_1403-40delTTTT		intron	N/A	NP_005262.1
	GLUD1	NM_001318900.1		c.1004-43_1004-40delTTTT		intron	N/A	NP_001305829.1
	GLUD1	NM_001318901.1		c.902-43_902-40delTTTT		intron	N/A	NP_001305830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1403-43_1403-40delTTTT		intron	N/A	ENSP00000277865.4
	GLUD1	ENST00000684338.1		c.1403-43_1403-40delTTTT		intron	N/A	ENSP00000507457.1
	GLUD1	ENST00000684201.1		c.1127-43_1127-40delTTTT		intron	N/A	ENSP00000507887.1

Frequencies

GnomAD3 genomes AF: 0.00000784 AC: 1 AN: 127606 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.0000175

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000478 AC: 284 AN: 593826 Hom.: 0 AF XY: 0.000453 AC XY: 146 AN XY: 322048

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

African (AFR) AF: 0.000845 AC: 13 AN: 15384

American (AMR) AF: 0.000609 AC: 20 AN: 32866

Ashkenazi Jewish (ASJ) AF: 0.000487 AC: 9 AN: 18474

East Asian (EAS) AF: 0.000662 AC: 21 AN: 31732

South Asian (SAS) AF: 0.000146 AC: 9 AN: 61792

European-Finnish (FIN) AF: 0.000351 AC: 13 AN: 37036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2486

European-Non Finnish (NFE) AF: 0.000514 AC: 187 AN: 363738

Other (OTH) AF: 0.000396 AC: 12 AN: 30318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000784 AC: 1 AN: 127606 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 61312

African (AFR) AF: 0.00 AC: 0 AN: 36212

American (AMR) AF: 0.00 AC: 0 AN: 12990

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: 0.0000175 AC: 1 AN: 57172

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

Alfa AF: 0.00 Hom.: 150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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

Other links and lift over

dbSNP: rs35186250; hg19: chr10-88817578;