15-86247682-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001386094.1(AGBL1):c.538C>T(p.Arg180Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,605,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1968134).
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL1	NM_001386094.1	c.538C>T	p.Arg180Cys	missense_variant	7/23	ENST00000614907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL1	ENST00000614907.3	c.538C>T	p.Arg180Cys	missense_variant	7/23	5	NM_001386094.1	P4
AGBL1	ENST00000441037.7	c.538C>T	p.Arg180Cys	missense_variant	7/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000149 AC: 35 AN: 234520 Hom.: 1 AF XY: 0.000102 AC XY: 13 AN XY: 127204

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 247 AN: 1453638 Hom.: 1 Cov.: 32 AF XY: 0.000141 AC XY: 102 AN XY: 722314

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74472

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.000473 AC: 2

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.400C>T (p.R134C) alteration is located in exon 6 (coding exon 5) of the AGBL1 gene. This alteration results from a C to T substitution at nucleotide position 400, causing the arginine (R) at amino acid position 134 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	0.90	D;D
PrimateAI	Uncertain	0.66	T
REVEL	Uncertain	0.39
Polyphen		1.0	.;D
MVP		0.56
MPC		0.011
ClinPred		0.54	D
GERP RS		4.2
Varity_R		0.21
gMVP		0.31

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: rs375019409; hg19: chr15-86790913;