Genetic Variant GLUD1:c.1403-41_1403-40dupTT (chr10-87057821-G-GAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_005271.5(GLUD1):c.1403-41_1403-40dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.000031 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0022 ( 0 hom. )

Consequence

GLUD1
NM_005271.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.237

Publications

1 publications found

Variant links:

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

GLUD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLUD1	NM_005271.5	MANE Select	c.1403-41_1403-40dupTT	intron	N/A	NP_005262.1	P00367-1
GLUD1	NM_001318900.1		c.1004-41_1004-40dupTT	intron	N/A	NP_001305829.1	P00367-3
GLUD1	NM_001318901.1		c.902-41_902-40dupTT	intron	N/A	NP_001305830.1	P00367-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1403-40_1403-39insTT	intron	N/A	ENSP00000277865.4	P00367-1
GLUD1	ENST00000915201.1		c.1451-40_1451-39insTT	intron	N/A	ENSP00000585260.1
GLUD1	ENST00000898383.1		c.1442-40_1442-39insTT	intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes

AF:

0.0000313

AC:

AN:

127594

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000700

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00222

AC:

1313

AN:

590470

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

722

AN XY:

320098

show subpopulations

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

African (AFR)

AF:

0.000456

AC:

AN:

15362

American (AMR)

AF:

0.00137

AC:

AN:

32812

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

AN:

18318

East Asian (EAS)

AF:

0.000691

AC:

AN:

31826

South Asian (SAS)

AF:

0.00240

AC:

147

AN:

61144

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

36922

Middle Eastern (MID)

AF:

0.00403

AC:

AN:

2480

European-Non Finnish (NFE)

AF:

0.00241

AC:

871

AN:

361430

Other (OTH)

AF:

0.00205

AC:

AN:

30176

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

155

311

466

622

777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000313

AC:

AN:

127594

Hom.:

Cov.:

AF XY:

0.0000652

AC XY:

AN XY:

61306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36212

American (AMR)

AF:

0.00

AC:

AN:

12992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3006

East Asian (EAS)

AF:

0.00

AC:

AN:

4744

South Asian (SAS)

AF:

0.00

AC:

AN:

3888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.0000700

AC:

AN:

57160

Other (OTH)

AF:

0.00

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over