rs756647962

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7

The NM_005271.5(GLUD1):c.585T>C(p.Asp195Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,558,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GLUD1
NM_005271.5 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.504

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 10-87074612-A-G is Benign according to our data. Variant chr10-87074612-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.504 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLUD1	NM_005271.5	MANE Select	c.585T>C	p.Asp195Asp	splice_region synonymous	Exon 4 of 13	NP_005262.1
GLUD1	NM_001318900.1		c.186T>C	p.Asp62Asp	splice_region synonymous	Exon 4 of 13	NP_001305829.1
GLUD1	NM_001318901.1		c.84T>C	p.Asp28Asp	splice_region synonymous	Exon 7 of 16	NP_001305830.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.585T>C	p.Asp195Asp	splice_region synonymous	Exon 4 of 13	ENSP00000277865.4
GLUD1	ENST00000684338.1		c.585T>C	p.Asp195Asp	splice_region synonymous	Exon 4 of 13	ENSP00000507457.1
GLUD1	ENST00000684201.1		c.585T>C	p.Asp195Asp	splice_region synonymous	Exon 4 of 11	ENSP00000507887.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000168

AC:

AN:

249796

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1406390

Hom.:

Cov.:

AF XY:

0.0000242

AC XY:

AN XY:

702938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32366

American (AMR)

AF:

0.00115

AC:

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25762

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062376

Other (OTH)

AF:

0.00

AC:

AN:

58386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000525

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41582

American (AMR)

AF:

0.000458

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000434

Hom.:

Bravo

AF:

0.0000945

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GLUD1-related disorder (1)

Hyperinsulinism-hyperammonemia syndrome (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.50

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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over