10-87052989-G-C

Variant names:

• chr10-87052989-G-C
• rs4934292
• NM_005271.5:c.1557+353C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000277865.5(GLUD1):​c.1557+353C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 151,990 control chromosomes in the GnomAD database, including 36,528 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (36528 hom., cov: 31)
• Consequence: GLUD1 ENST00000277865.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000277865.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	NM_005271.5	MANE Select	c.1557+353C>G		intron	N/A	NP_005262.1
	GLUD1	NM_001318900.1		c.1158+353C>G		intron	N/A	NP_001305829.1
	GLUD1	NM_001318901.1		c.1056+353C>G		intron	N/A	NP_001305830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1557+353C>G		intron	N/A	ENSP00000277865.4
	GLUD1	ENST00000684338.1		c.*36+275C>G		intron	N/A	ENSP00000507457.1
	GLUD1	ENST00000684201.1		c.1281+353C>G		intron	N/A	ENSP00000507887.1

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104442 AN: 151872 Hom.: 36467 Cov.: 31

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.678

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.688 AC: 104560 AN: 151990 Hom.: 36528 Cov.: 31 AF XY: 0.689 AC XY: 51163 AN XY: 74292

African (AFR) AF: 0.803 AC: 33274 AN: 41458

American (AMR) AF: 0.721 AC: 11007 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2256 AN: 3470

East Asian (EAS) AF: 0.777 AC: 4009 AN: 5158

South Asian (SAS) AF: 0.559 AC: 2687 AN: 4810

European-Finnish (FIN) AF: 0.660 AC: 6972 AN: 10556

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42076 AN: 67960

Other (OTH) AF: 0.683 AC: 1442 AN: 2112

Alfa AF: 0.652 Hom.: 4056

Bravo AF: 0.703

Asia WGS AF: 0.673 AC: 2341 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.37
DANN	Benign	0.43
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs4934292; hg19: chr10-88812746;