15-86247678-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386094.1(AGBL1):c.534C>G(p.Asn178Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N178N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL1	NM_001386094.1	c.534C>G	p.Asn178Lys	missense_variant	7/23	ENST00000614907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL1	ENST00000614907.3	c.534C>G	p.Asn178Lys	missense_variant	7/23	5	NM_001386094.1	P4
AGBL1	ENST00000441037.7	c.534C>G	p.Asn178Lys	missense_variant	7/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450934 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

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

Dec 11, 2023

The c.396C>G (p.N132K) alteration is located in exon 6 (coding exon 5) of the AGBL1 gene. This alteration results from a C to G substitution at nucleotide position 396, causing the asparagine (N) at amino acid position 132 to be replaced by a lysine (K). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T;.
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.56	T
REVEL	Benign	0.27
Polyphen		1.0	.;D
MutPred		0.50		.;Gain of catalytic residue at N132 (P = 0.087);
MVP		0.51
MPC		0.046
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.042
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370819428; hg19: chr15-86790909;