10-87050580-TAAAAAAAA-TAAAAAAAAA

Variant names:

• chr10-87050580-T-TA
• rs80258277
• NM_005271.5:c.*1170dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005271.5(GLUD1):​c.*1170dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 136,270 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.018 (30 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GLUD1 NM_005271.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510
• 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, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0177 (2409/136270) while in subpopulation AFR AF = 0.0391 (1452/37138). AF 95% confidence interval is 0.0374. There are 30 homozygotes in GnomAd4. There are 1186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

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.*1170dupT		3_prime_UTR	Exon 13 of 13	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.*1170dupT		3_prime_UTR	Exon 13 of 13	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.*1170dupT		3_prime_UTR	Exon 16 of 16	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.*1170dupT		3_prime_UTR	Exon 13 of 13	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.*1170dupT		3_prime_UTR	Exon 13 of 13	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.*1170dupT		3_prime_UTR	Exon 13 of 13	ENSP00000568442.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2407 AN: 136254 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00895

Gnomad EAS AF: 0.00378

Gnomad SAS AF: 0.00325

Gnomad FIN AF: 0.00742

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.0153

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0177 AC: 2409 AN: 136270 Hom.: 30 Cov.: 32 AF XY: 0.0180 AC XY: 1186 AN XY: 65916

African (AFR) AF: 0.0391 AC: 1452 AN: 37138

American (AMR) AF: 0.0207 AC: 281 AN: 13584

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 29 AN: 3242

East Asian (EAS) AF: 0.00379 AC: 18 AN: 4752

South Asian (SAS) AF: 0.00327 AC: 14 AN: 4286

European-Finnish (FIN) AF: 0.00742 AC: 59 AN: 7954

Middle Eastern (MID) AF: 0.0113 AC: 3 AN: 266

European-Non Finnish (NFE) AF: 0.00816 AC: 509 AN: 62360

Other (OTH) AF: 0.0153 AC: 28 AN: 1836

Alfa AF: 0.000250 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperinsulinism, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.051
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: rs80258277; hg19: chr10-88810337;