7-135034379-T-G

Variant summary

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

The NM_178563.4(AGBL3):c.788T>G(p.Ile263Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGBL3 NM_178563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL3	NM_178563.4	c.788T>G	p.Ile263Ser	missense_variant	7/17	ENST00000436302.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL3	ENST00000436302.6	c.788T>G	p.Ile263Ser	missense_variant	7/17	2	NM_178563.4	P2
AGBL3	ENST00000275763.10	c.788T>G	p.Ile263Ser	missense_variant, NMD_transcript_variant	7/17	1
AGBL3	ENST00000435976.6	c.788T>G	p.Ile263Ser	missense_variant	7/16	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399360 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690180

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: 9.27e-7

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

Sep 25, 2023

The c.788T>G (p.I263S) alteration is located in exon 7 (coding exon 6) of the AGBL3 gene. This alteration results from a T to G substitution at nucleotide position 788, causing the isoleucine (I) at amino acid position 263 to be replaced by a serine (S). 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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.85	P;.
Vest4		0.90
MutPred		0.52		Gain of disorder (P = 0.0042);Gain of disorder (P = 0.0042);
MVP		0.088
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-134719130;