dbSNP rs550609501: GLUD1:c.1403-5delT (chr10-87057786-CA-C) – 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.1403-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,240,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GLUD1
NM_005271.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0140

Publications

0 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5 link	c.1403-5delT		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000277865.5	NP_005262.1	P00367-1E9KL48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5 link	c.1403-5delT		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_005271.5	ENSP00000277865.4		P00367-1

Frequencies

GnomAD3 genomes

AF:

0.00000794

AC:

AN:

125924

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:

0.0000172

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000126

AC:

AN:

1114350

Hom.:

Cov.:

AF XY:

0.00000706

AC XY:

AN XY:

566926

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26590

American (AMR)

AF:

0.00

AC:

AN:

41944

Ashkenazi Jewish (ASJ)

AF:

0.0000449

AC:

AN:

22284

East Asian (EAS)

AF:

0.00

AC:

AN:

35814

South Asian (SAS)

AF:

0.00

AC:

AN:

74906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4674

European-Non Finnish (NFE)

AF:

0.0000160

AC:

AN:

810790

Other (OTH)

AF:

0.00

AC:

AN:

47664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000137779), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.282

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:

0.00000794

AC:

AN:

125924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33976

American (AMR)

AF:

0.00

AC:

AN:

12412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3088

East Asian (EAS)

AF:

0.00

AC:

AN:

4474

South Asian (SAS)

AF:

0.00

AC:

AN:

3892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

58306

Other (OTH)

AF:

0.00

AC:

AN:

1680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.014

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over