10-87057821-GAAAAAA-GAAAAAAA

Variant names:

• chr10-87057821-G-GA
• rs35186250
• NM_005271.5:c.1403-40dupT

Variant summary

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

The NM_005271.5(GLUD1):​c.1403-40dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.081 (0 hom.)
• 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.1403-40dupT		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_1403-39insT		intron_variant	Intron 10 of 12	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 178 AN: 127562 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000847

Gnomad ASJ AF: 0.00133

Gnomad EAS AF: 0.00148

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00375

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00118

GnomAD4 exome AF: 0.0811 AC: 45837 AN: 565458 Hom.: 0 Cov.: 0 AF XY: 0.0817 AC XY: 24955 AN XY: 305584

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

African (AFR) AF: 0.0376 AC: 569 AN: 15120

American (AMR) AF: 0.0470 AC: 1498 AN: 31878

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 1885 AN: 17464

East Asian (EAS) AF: 0.0218 AC: 686 AN: 31438

South Asian (SAS) AF: 0.100 AC: 5602 AN: 55896

European-Finnish (FIN) AF: 0.0731 AC: 2612 AN: 35752

Middle Eastern (MID) AF: 0.0843 AC: 198 AN: 2350

European-Non Finnish (NFE) AF: 0.0881 AC: 30555 AN: 346640

Other (OTH) AF: 0.0772 AC: 2232 AN: 28920

⚠️ 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: 0.00140 AC: 179 AN: 127592 Hom.: 0 Cov.: 0 AF XY: 0.00153 AC XY: 94 AN XY: 61336

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

African (AFR) AF: 0.000358 AC: 13 AN: 36274

American (AMR) AF: 0.000846 AC: 11 AN: 13006

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 4 AN: 3004

East Asian (EAS) AF: 0.00169 AC: 8 AN: 4728

South Asian (SAS) AF: 0.00129 AC: 5 AN: 3868

European-Finnish (FIN) AF: 0.00375 AC: 26 AN: 6940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00193 AC: 110 AN: 57128

Other (OTH) AF: 0.00117 AC: 2 AN: 1706

⚠️ 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.

Alfa AF: 0.000405 Hom.: 150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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;