dbSNP rs141844887: GLUD1:p.Thr490Thr (chr10-87057715-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005271.5(GLUD1):c.1470G>A(p.Thr490Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,588,530 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T490T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0077 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 17 hom. )

Consequence

GLUD1
NM_005271.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.366

Publications

3 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 10-87057715-C-T is Benign according to our data. Variant chr10-87057715-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.366 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00766 (1164/151980) while in subpopulation AFR AF = 0.027 (1120/41434). AF 95% confidence interval is 0.0257. There are 17 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1164 AD gene.

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	UniProt
GLUD1	NM_005271.5	MANE Select	c.1470G>A	p.Thr490Thr	synonymous	Exon 11 of 13	NP_005262.1	P00367-1
GLUD1	NM_001318900.1		c.1071G>A	p.Thr357Thr	synonymous	Exon 11 of 13	NP_001305829.1	P00367-3
GLUD1	NM_001318901.1		c.969G>A	p.Thr323Thr	synonymous	Exon 14 of 16	NP_001305830.1	P00367-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1470G>A	p.Thr490Thr	synonymous	Exon 11 of 13	ENSP00000277865.4	P00367-1
GLUD1	ENST00000915201.1		c.1518G>A	p.Thr506Thr	synonymous	Exon 11 of 13	ENSP00000585260.1
GLUD1	ENST00000898383.1		c.1509G>A	p.Thr503Thr	synonymous	Exon 11 of 13	ENSP00000568442.1

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

1161

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.00197

AC:

495

AN:

251464

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000775

AC:

1114

AN:

1436550

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

473

AN XY:

716204

show subpopulations

African (AFR)

AF:

0.0267

AC:

879

AN:

32976

American (AMR)

AF:

0.000984

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39582

South Asian (SAS)

AF:

0.000175

AC:

AN:

85698

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0000422

AC:

AN:

1089040

Other (OTH)

AF:

0.00188

AC:

112

AN:

59532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00766

AC:

1164

AN:

151980

Hom.:

Cov.:

AF XY:

0.00756

AC XY:

561

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.0270

AC:

1120

AN:

41434

American (AMR)

AF:

0.00184

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67988

Other (OTH)

AF:

0.00381

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00330

Hom.:

Bravo

AF:

0.00829

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hyperinsulinism-hyperammonemia syndrome (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

3.5

(source)

DANN

Benign

0.71

PhyloP100

-0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Computational scores

Splicing

Publications

Other links and lift over