15-86674435-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001386094.1(AGBL1):c.3157C>T(p.Arg1053Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,603,274 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

AGBL1
NM_001386094.1 missense, splice_region

Scores

Splicing: ADA: 0.00008529

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: -0.0460

Publications

17 publications found

Variant links:

Genes affected

AGBL1 (HGNC:26504): (AGBL carboxypeptidase 1) Polyglutamylation is a reversible posttranslational modification catalyzed by polyglutamylases that results in the addition of glutamate side chains on the modified protein. This gene encodes a glutamate decarboxylase that catalyzes the deglutamylation of polyglutamylated proteins. Mutations in this gene result in dominant late-onset Fuchs corneal dystrophy. [provided by RefSeq, Nov 2013]

AGBL1 Gene-Disease associations (from GenCC):

Fuchs' endothelial dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
corneal dystrophy, Fuchs endothelial, 8
Inheritance: AD Classification: LIMITED Submitted by: G2P

AGBL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00622347).

BS2

High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGBL1	NM_001386094.1 link	c.3157C>T	p.Arg1053Trp	missense_variant, splice_region_variant	Exon 22 of 23	ENST00000614907.3	NP_001373023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGBL1	ENST00000614907.3 link	c.3157C>T	p.Arg1053Trp	missense_variant, splice_region_variant	Exon 22 of 23	5	NM_001386094.1	ENSP00000490608.2
AGBL1	ENST00000441037.7 link	c.3220C>T	p.Arg1074*	stop_gained, splice_region_variant	Exon 23 of 25	5		ENSP00000413001.3
AGBL1	ENST00000681381.1 link	n.316C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

297

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00179

AC:

440

AN:

245850

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.00899

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.00241

AC:

3498

AN:

1450998

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1689

AN XY:

719672

show subpopulations

African (AFR)

AF:

0.000421

AC:

AN:

33284

American (AMR)

AF:

0.00139

AC:

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.00896

AC:

233

AN:

25994

East Asian (EAS)

AF:

0.000102

AC:

AN:

39290

South Asian (SAS)

AF:

0.000151

AC:

AN:

85844

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.000392

AC:

AN:

5098

European-Non Finnish (NFE)

AF:

0.00273

AC:

3016

AN:

1103956

Other (OTH)

AF:

0.00254

AC:

152

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

166

331

497

662

828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00195

AC:

297

AN:

152276

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41554

American (AMR)

AF:

0.00340

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00272

AC:

185

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00257

Hom.:

Bravo

AF:

0.00223

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000767

AC:

ESP6500EA

AF:

0.00350

AC:

ExAC

AF:

0.00170

AC:

206

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00290

EpiControl

AF:

0.00286

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 8

Pathogenic:1Uncertain:2

Aug 03, 2023

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_152336.2:c.3082C>T in the AGBL1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in a family with late-onset fuchs corneal dystrophy, and segregated with an FCD haplotype in the family (PMID: 24094747). However, loss-of-function variants of the AGBL1 gene are common in gnomAD, which is unusual for AD inheritance manner. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in AGBL1 cause disease. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP1, PP4, BS1. -

Oct 03, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

AGBL1-related disorder

Uncertain:1

Jul 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AGBL1 c.3220C>T variant is predicted to result in premature protein termination (p.Arg1074*). This variant has been reported in individuals with late-onset Fuchs corneal dystrophy (reported as c.3082C>T [p.Arg1028*] in Riazuddin et al. 2013. PubMed ID: 24094747; Zhang et al. 2019. PubMed ID: 31555324). However, in the Riazuddin et al. study, the variant did not entirely segregate with disease in a large pedigree. This variant is documented to occur globally in 0.18% of alleles and up to 0.92% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is more frequent than expected for a pathogenic variant. Additionally, loss of function variants including nonsense variants are predicted to be highly tolerated by the ExAC loss of function calculations (Lek et al. 2016. PubMed ID: 27535533). Given the conflicting evidence, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fuchs' endothelial dystrophy

Uncertain:1

Apr 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.85

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0062

PhyloP100

-0.046

GERP RS

-11

Mutation Taster

=19/181

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000085

dbscSNV1_RF

Benign

0.17

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over