15-86158987-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001386094.1(AGBL1):c.449T>C(p.Val150Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37870798).
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL1	NM_001386094.1	c.449T>C	p.Val150Ala	missense_variant	5/23	ENST00000614907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL1	ENST00000614907.3	c.449T>C	p.Val150Ala	missense_variant	5/23	5	NM_001386094.1	P4
AGBL1	ENST00000441037.7	c.449T>C	p.Val150Ala	missense_variant	5/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 248786 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461074 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

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: 0.00

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

Nov 19, 2022

The c.311T>C (p.V104A) alteration is located in exon 4 (coding exon 3) of the AGBL1 gene. This alteration results from a T to C substitution at nucleotide position 311, causing the valine (V) at amino acid position 104 to be replaced by an alanine (A). 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	0.34
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T;.
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.22
Polyphen		0.81	.;P
MutPred		0.34		.;Loss of stability (P = 0.0145);
MVP		0.26
MPC		0.031
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.057
gMVP		0.25

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: rs1307320647; hg19: chr15-86702218;