7-135034478-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178563.4(AGBL3):c.887C>T(p.Ala296Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGBL3 NM_178563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

Genes affected

AGBL3 (HGNC:27981): (AGBL carboxypeptidase 3) Enables metallocarboxypeptidase activity. Involved in protein side chain deglutamylation. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL3	NM_178563.4	c.887C>T	p.Ala296Val	missense_variant	7/17	ENST00000436302.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL3	ENST00000436302.6	c.887C>T	p.Ala296Val	missense_variant	7/17	2	NM_178563.4	P2
AGBL3	ENST00000275763.10	c.887C>T	p.Ala296Val	missense_variant, NMD_transcript_variant	7/17	1
AGBL3	ENST00000435976.6	c.887C>T	p.Ala296Val	missense_variant	7/16	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

Mar 17, 2023

The c.887C>T (p.A296V) alteration is located in exon 7 (coding exon 6) of the AGBL3 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the alanine (A) at amino acid position 296 to be replaced by a valine (V). 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
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.65		Loss of catalytic residue at A296 (P = 0.1474);Loss of catalytic residue at A296 (P = 0.1474);
MVP		0.13
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.87

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: rs1423530860; hg19: chr7-134719229;