chr10-87057821-G-GAAA

Variant names:

• chr10-87057821-G-GAAA
• rs35186250
• NM_005271.5:c.1403-42_1403-40dupTTT

Variant summary

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

The NM_005271.5(GLUD1):​c.1403-42_1403-40dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 0 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	NM_005271.5	MANE Select	c.1403-42_1403-40dupTTT		intron	N/A	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.1004-42_1004-40dupTTT		intron	N/A	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.902-42_902-40dupTTT		intron	N/A	NP_001305830.1	P00367-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1403-40_1403-39insTTT		intron	N/A	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.1451-40_1451-39insTTT		intron	N/A	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.1442-40_1442-39insTTT		intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.000165 AC: 98 AN: 594814 Hom.: 0 Cov.: 0 AF XY: 0.000158 AC XY: 51 AN XY: 322568

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

African (AFR) AF: 0.000195 AC: 3 AN: 15414

American (AMR) AF: 0.0000910 AC: 3 AN: 32950

Ashkenazi Jewish (ASJ) AF: 0.000324 AC: 6 AN: 18500

East Asian (EAS) AF: 0.0000314 AC: 1 AN: 31874

South Asian (SAS) AF: 0.000210 AC: 13 AN: 61784

European-Finnish (FIN) AF: 0.0000539 AC: 2 AN: 37122

Middle Eastern (MID) AF: 0.000401 AC: 1 AN: 2492

European-Non Finnish (NFE) AF: 0.000181 AC: 66 AN: 364300

Other (OTH) AF: 0.0000988 AC: 3 AN: 30378

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;