dbSNP rs17096421: GLUD1:c.1060-10T>A (chr10-87060835-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005271.5(GLUD1):c.1060-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,614,148 control chromosomes in the GnomAD database, including 2,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 122 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1897 hom. )

Consequence

GLUD1
NM_005271.5 intron

Scores

Splicing: ADA: 0.4035

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.931

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 10-87060835-A-T is Benign according to our data. Variant chr10-87060835-A-T is described in ClinVar as Benign. ClinVar VariationId is 129162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

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.1060-10T>A	intron	N/A	NP_005262.1	P00367-1
GLUD1	NM_001318900.1		c.661-10T>A	intron	N/A	NP_001305829.1	P00367-3
GLUD1	NM_001318901.1		c.559-10T>A	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.1060-10T>A	intron	N/A	ENSP00000277865.4	P00367-1
GLUD1	ENST00000915201.1		c.1108-10T>A	intron	N/A	ENSP00000585260.1
GLUD1	ENST00000898383.1		c.1099-10T>A	intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4762

AN:

152176

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00927

Gnomad AMI

AF:

0.179

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0336

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0505

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0299

AC:

7521

AN:

251470

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.00991

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0353

Gnomad NFE exome

AF:

0.0480

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0463

AC:

67662

AN:

1461854

Hom.:

1897

Cov.:

AF XY:

0.0447

AC XY:

32539

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00830

AC:

278

AN:

33480

American (AMR)

AF:

0.0111

AC:

497

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

732

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0126

AC:

1085

AN:

86258

European-Finnish (FIN)

AF:

0.0345

AC:

1842

AN:

53420

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0547

AC:

60778

AN:

1111976

Other (OTH)

AF:

0.0399

AC:

2409

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3766

7532

11299

15065

18831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2292

4584

6876

9168

11460

<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:

0.0313

AC:

4764

AN:

152294

Hom.:

122

Cov.:

AF XY:

0.0300

AC XY:

2232

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00924

AC:

384

AN:

41568

American (AMR)

AF:

0.0158

AC:

242

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0112

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0336

AC:

356

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0505

AC:

3433

AN:

68036

Other (OTH)

AF:

0.0180

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

233

466

700

933

1166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0368

Hom.:

Bravo

AF:

0.0295

ClinVar

ClinVar submissions

Significance: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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.93

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.40

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -10

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