Genetic Variant GLUD1:c.1403-44_1403-40delTTTTT (chr10-87057821-GAAAAA-G) – 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.1403-44_1403-40delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 722,742 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

GLUD1
NM_005271.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

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, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

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
GLUD1	NM_005271.5	MANE Select	c.1403-44_1403-40delTTTTT	intron	N/A	NP_005262.1
GLUD1	NM_001318900.1		c.1004-44_1004-40delTTTTT	intron	N/A	NP_001305829.1
GLUD1	NM_001318901.1		c.902-44_902-40delTTTTT	intron	N/A	NP_001305830.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1403-44_1403-40delTTTTT	intron	N/A	ENSP00000277865.4
GLUD1	ENST00000684338.1		c.1403-44_1403-40delTTTTT	intron	N/A	ENSP00000507457.1
GLUD1	ENST00000684201.1		c.1127-44_1127-40delTTTTT	intron	N/A	ENSP00000507887.1

Frequencies

GnomAD3 genomes

AF:

0.0000470

AC:

AN:

127608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000552

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:

0.000144

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000350

Gnomad OTH

AF:

0.000591

GnomAD4 exome

AF:

0.0000622

AC:

AN:

595102

Hom.:

AF XY:

0.0000434

AC XY:

AN XY:

322720

show subpopulations

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

African (AFR)

AF:

0.000195

AC:

AN:

15414

American (AMR)

AF:

0.0000607

AC:

AN:

32948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18522

East Asian (EAS)

AF:

0.0000942

AC:

AN:

31862

South Asian (SAS)

AF:

0.0000162

AC:

AN:

61840

European-Finnish (FIN)

AF:

0.000108

AC:

AN:

37150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2492

European-Non Finnish (NFE)

AF:

0.0000494

AC:

AN:

364488

Other (OTH)

AF:

0.000197

AC:

AN:

30386

⚠️ 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: 0.293

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000470

AC:

AN:

127640

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

61360

show subpopulations

African (AFR)

AF:

0.0000551

AC:

AN:

36278

American (AMR)

AF:

0.00

AC:

AN:

13008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3006

East Asian (EAS)

AF:

0.00

AC:

AN:

4728

South Asian (SAS)

AF:

0.00

AC:

AN:

3868

European-Finnish (FIN)

AF:

0.000144

AC:

AN:

6948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.0000350

AC:

AN:

57160

Other (OTH)

AF:

0.000586

AC:

AN:

1706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over