10-87074567-T-A

Variant names:

• chr10-87074567-T-A
• NM_005271.5:c.630A>T
• GLUD1 p.Ala210Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005271.5(GLUD1):​c.630A>T​(p.Ala210Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A210A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLUD1 NM_005271.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201
• 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=0.201 with no splicing effect.

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.630A>T	p.Ala210Ala	synonymous	Exon 4 of 13	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.231A>T	p.Ala77Ala	synonymous	Exon 4 of 13	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.129A>T	p.Ala43Ala	synonymous	Exon 7 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.630A>T	p.Ala210Ala	synonymous	Exon 4 of 13	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.630A>T	p.Ala210Ala	synonymous	Exon 4 of 13	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.630A>T	p.Ala210Ala	synonymous	Exon 4 of 13	ENSP00000568442.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.3
DANN	Benign	0.73
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-88834324;