chr7-135032871-C-G

Position:

• chr7-135032871-C-G

Variant summary

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

The NM_178563.4(AGBL3):​c.446C>G​(p.Ser149Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000644 in 1,397,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: AGBL3 NM_178563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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]

AGBL3 (HGNC:):

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	Protein	UniProt
AGBL3	NM_178563.4	c.446C>G	p.Ser149Cys	missense_variant	6/17	ENST00000436302.6	NP_848658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGBL3	ENST00000436302.6	c.446C>G	p.Ser149Cys	missense_variant	6/17	2	NM_178563.4	ENSP00000388275.2
AGBL3	ENST00000275763.10	n.446C>G		non_coding_transcript_exon_variant	6/17	1		ENSP00000275763.6
AGBL3	ENST00000435976.6	c.446C>G	p.Ser149Cys	missense_variant	6/16	5		ENSP00000401220.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1397846 Hom.: 0 Cov.: 30 AF XY: 0.00000435 AC XY: 3 AN XY: 689360

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: 0.00000835

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Oct 26, 2022

The c.446C>G (p.S149C) alteration is located in exon 6 (coding exon 5) of the AGBL3 gene. This alteration results from a C to G substitution at nucleotide position 446, causing the serine (S) at amino acid position 149 to be replaced by a cysteine (C). 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	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.51		Loss of catalytic residue at S149 (P = 0.0383);Loss of catalytic residue at S149 (P = 0.0383);
MVP		0.25
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.45

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: rs1815915465; hg19: chr7-134717622;