7-135134950-T-C

Position:

• chr7-135134950-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178563.4(AGBL3):​c.2452T>C​(p.Trp818Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGBL3 NM_178563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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]

CYREN (HGNC:):

CYREN (HGNC:22432): (cell cycle regulator of NHEJ) Involved in double-strand break repair via nonhomologous end joining and negative regulation of double-strand break repair via nonhomologous end joining. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0564332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGBL3	NM_178563.4	c.2452T>C	p.Trp818Arg	missense_variant	17/17	ENST00000436302.6	NP_848658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGBL3	ENST00000436302.6	c.2452T>C	p.Trp818Arg	missense_variant	17/17	2	NM_178563.4	ENSP00000388275.2
CYREN	ENST00000459937.5	n.356+33799A>G		intron_variant		1
AGBL3	ENST00000435976.6	c.2111-12863T>C		intron_variant		5		ENSP00000401220.2
CYREN	ENST00000464070.1	n.187+13027A>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 20, 2024

The c.2452T>C (p.W818R) alteration is located in exon 17 (coding exon 16) of the AGBL3 gene. This alteration results from a T to C substitution at nucleotide position 2452, causing the tryptophan (W) at amino acid position 818 to be replaced by an arginine (R). 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	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.83
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.37		Gain of disorder (P = 0.0113);
MVP		0.088
ClinPred		0.18	T
GERP RS		1.1
gMVP		0.21

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: chr7-134819702;