NM_005271.5:c.445+3928C>T

Variant names:

• chr10-87090397-G-A
• rs1923934
• NM_005271.5:c.445+3928C>T

Variant summary

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

The NM_005271.5(GLUD1):​c.445+3928C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,000 control chromosomes in the GnomAD database, including 6,631 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 0.28 (6631 hom., cov: 32)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

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.445+3928C>T		intron	N/A	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.46+3536C>T		intron	N/A	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.-283-609C>T		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.445+3928C>T		intron	N/A	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.445+3928C>T		intron	N/A	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.445+3928C>T		intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42922 AN: 151888 Hom.: 6619 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.267

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

GnomAD4 genome AF: 0.283 AC: 42978 AN: 152000 Hom.: 6631 Cov.: 32 AF XY: 0.286 AC XY: 21257 AN XY: 74250

African (AFR) AF: 0.241 AC: 9973 AN: 41440

American (AMR) AF: 0.327 AC: 5001 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3472

East Asian (EAS) AF: 0.711 AC: 3668 AN: 5162

South Asian (SAS) AF: 0.186 AC: 895 AN: 4820

European-Finnish (FIN) AF: 0.313 AC: 3291 AN: 10530

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18472 AN: 67986

Other (OTH) AF: 0.269 AC: 570 AN: 2116

Alfa AF: 0.272 Hom.: 746

Bravo AF: 0.288

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.66
PhyloP100		0.35
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: rs1923934; hg19: chr10-88850154;