15-86257996-G-T

Variant summary

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

The NM_001386094.1(AGBL1):c.934G>T(p.Asp312Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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.934G>T	p.Asp312Tyr	missense_variant	9/23	ENST00000614907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL1	ENST00000614907.3	c.934G>T	p.Asp312Tyr	missense_variant	9/23	5	NM_001386094.1	P4
AGBL1	ENST00000441037.7	c.934G>T	p.Asp312Tyr	missense_variant	9/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 16, 2024

The c.796G>T (p.D266Y) alteration is located in exon 8 (coding exon 7) of the AGBL1 gene. This alteration results from a G to T substitution at nucleotide position 796, causing the aspartic acid (D) at amino acid position 266 to be replaced by a tyrosine (Y). 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	0.14
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;.
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.63	N;N
PrimateAI	Benign	0.39	T
REVEL	Benign	0.23
Polyphen		1.0	.;D
MutPred		0.21		.;Gain of phosphorylation at D266 (P = 0.0033);
MVP		0.46
MPC		0.061
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-86801227; COSMIC: COSV66853136; COSMIC: COSV66853136;