rs185919705

Positions:

chr15-86674435-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_152336.4(AGBL1):c.3220C>T(p.Arg1074*) variant causes a stop gained, 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

AGBL1
NM_152336.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.00008529

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:3

Conservation

PhyloP100: -0.0460

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 links:

AGBL1 (HGNC:):

AGBL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGBL1	NM_001386094.1 linkuse as main transcript	c.3157C>T	p.Arg1053Trp	missense_variant, splice_region_variant	22/23	ENST00000614907.3	NP_001373023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGBL1	ENST00000614907.3 linkuse as main transcript	c.3157C>T	p.Arg1053Trp	missense_variant, splice_region_variant	22/23	5	NM_001386094.1	ENSP00000490608.2	A0A1B0GVQ2
AGBL1	ENST00000441037.7 linkuse as main transcript	c.3220C>T	p.Arg1074*	stop_gained, splice_region_variant	23/25	5		ENSP00000413001.3	Q96MI9
AGBL1	ENST00000681381.1 linkuse as main transcript	n.316C>T		splice_region_variant, non_coding_transcript_exon_variant	2/4

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

GnomAD3 exomes

AF:

0.00179

AC:

440

AN:

245850

Hom.:

AF XY:

0.00187

AC XY:

250

AN XY:

133370

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 SAS exome

AF:

0.0000989

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

Gnomad4 AFR exome

AF:

0.000421

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00896

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00273

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00195

AC:

297

AN:

152276

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00272

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00268

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:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 8

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 03, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Aug 03, 2023	- -

AGBL1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 04, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

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

GERP RS

-11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over