10-87057821-GAAAAAA-GAAAA

Variant names:

• chr10-87057821-GAA-G
• rs35186250
• NM_005271.5:c.1403-41_1403-40delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005271.5(GLUD1):​c.1403-41_1403-40delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 698,746 control chromosomes in the GnomAD database, including 19 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0093 (17 hom., cov: 0)
  • Exomes 𝑓: 0.038 (2 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00932 (1189/127596) while in subpopulation AFR AF = 0.0304 (1104/36272). AF 95% confidence interval is 0.0289. There are 17 homozygotes in GnomAd4. There are 575 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.1403-41_1403-40delTT		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.1403-41_1403-40delTT		intron_variant	Intron 10 of 12	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1186 AN: 127564 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00239

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00148

Gnomad SAS AF: 0.000772

Gnomad FIN AF: 0.000720

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000525

Gnomad OTH AF: 0.00473

GnomAD4 exome AF: 0.0383 AC: 21865 AN: 571150 Hom.: 2 AF XY: 0.0368 AC XY: 11396 AN XY: 309416

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

African (AFR) AF: 0.0920 AC: 1367 AN: 14854

American (AMR) AF: 0.0611 AC: 1933 AN: 31612

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 503 AN: 17780

East Asian (EAS) AF: 0.101 AC: 3035 AN: 30094

South Asian (SAS) AF: 0.0196 AC: 1164 AN: 59344

European-Finnish (FIN) AF: 0.0413 AC: 1474 AN: 35726

Middle Eastern (MID) AF: 0.0284 AC: 68 AN: 2392

European-Non Finnish (NFE) AF: 0.0317 AC: 11115 AN: 350158

Other (OTH) AF: 0.0413 AC: 1206 AN: 29190

⚠️ 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: 0.00932 AC: 1189 AN: 127596 Hom.: 17 Cov.: 0 AF XY: 0.00937 AC XY: 575 AN XY: 61336

African (AFR) AF: 0.0304 AC: 1104 AN: 36272

American (AMR) AF: 0.00238 AC: 31 AN: 13002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3002

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

South Asian (SAS) AF: 0.000776 AC: 3 AN: 3866

European-Finnish (FIN) AF: 0.000720 AC: 5 AN: 6942

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

European-Non Finnish (NFE) AF: 0.000525 AC: 30 AN: 57140

Other (OTH) AF: 0.00469 AC: 8 AN: 1706

Alfa AF: 0.00 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;