10-87057821-GAAAAAA-GAAA

Variant names:

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

Variant summary

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

The NM_005271.5(GLUD1):​c.1403-42_1403-40delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 716,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0040 (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 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_1403-40delTTT		intron	N/A	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.1004-42_1004-40delTTT		intron	N/A	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.902-42_902-40delTTT		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.1403-42_1403-40delTTT		intron	N/A	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.1451-42_1451-40delTTT		intron	N/A	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.1442-42_1442-40delTTT		intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes AF: 0.0000157 AC: 2 AN: 127588 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: 0.000144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000175

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00402 AC: 2364 AN: 588624 Hom.: 0 AF XY: 0.00378 AC XY: 1208 AN XY: 319228

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

African (AFR) AF: 0.00795 AC: 121 AN: 15228

American (AMR) AF: 0.00691 AC: 225 AN: 32562

Ashkenazi Jewish (ASJ) AF: 0.00278 AC: 51 AN: 18372

East Asian (EAS) AF: 0.00745 AC: 233 AN: 31282

South Asian (SAS) AF: 0.00170 AC: 104 AN: 61354

European-Finnish (FIN) AF: 0.00439 AC: 161 AN: 36702

Middle Eastern (MID) AF: 0.00285 AC: 7 AN: 2452

European-Non Finnish (NFE) AF: 0.00370 AC: 1335 AN: 360626

Other (OTH) AF: 0.00423 AC: 127 AN: 30046

⚠️ 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: 0.0000157 AC: 2 AN: 127620 Hom.: 0 Cov.: 0 AF XY: 0.0000163 AC XY: 1 AN XY: 61348

African (AFR) AF: 0.00 AC: 0 AN: 36276

American (AMR) AF: 0.00 AC: 0 AN: 13002

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4728

South Asian (SAS) AF: 0.00 AC: 0 AN: 3868

European-Finnish (FIN) AF: 0.000144 AC: 1 AN: 6944

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

European-Non Finnish (NFE) AF: 0.0000175 AC: 1 AN: 57152

Other (OTH) AF: 0.00 AC: 0 AN: 1706

Alfa AF: 0.00 Hom.: 150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;