rs181958589

Positions:

• chr15-86674322-G-C
• chr15-86674322-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001386094.1(AGBL1):​c.3044G>C​(p.Cys1015Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,612,102 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 5.91

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020041704).
• BP6: Variant 15-86674322-G-C is Benign according to our data. Variant chr15-86674322-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 88758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGBL1	NM_001386094.1	c.3044G>C	p.Cys1015Ser	missense_variant	22/23	ENST00000614907.3	NP_001373023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGBL1	ENST00000614907.3	c.3044G>C	p.Cys1015Ser	missense_variant	22/23	5	NM_001386094.1	ENSP00000490608.2
AGBL1	ENST00000441037.7	c.3107G>C	p.Cys1036Ser	missense_variant	23/25	5		ENSP00000413001.3
AGBL1	ENST00000681381.1	n.203G>C		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00119 AC: 291 AN: 244704 Hom.: 1 AF XY: 0.00128 AC XY: 170 AN XY: 132694

Gnomad AFR exome AF: 0.000400

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00117

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.00202 AC: 2949 AN: 1459780 Hom.: 4 Cov.: 42 AF XY: 0.00200 AC XY: 1453 AN XY: 725926

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000584

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00118 AC XY: 88 AN XY: 74488

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00130

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.00252 AC: 21

ExAC AF: 0.00126 AC: 152

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 8 Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 03, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Oct 08, 2024	The AGBL1 c.3044G>C (p.Cys1015Ser) variant (rs181958589) has been reported as likely benign by laboratories in ClinVar (Variation ID: 88758). GnomAD 4.1.0 frequency is 0.001952 with 6 homozygotes. This frequencyt and number of homozygotes are not compatible with a variant causing the disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

AGBL1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Uncertain	0.53	T
Polyphen		1.0	.;D;.
MutPred		0.76		.;Gain of disorder (P = 0.0257);.;
MVP		0.31
MPC		0.049
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs181958589; hg19: chr15-87217553;