7-135134894-C-T

Variant names:

• chr7-135134894-C-T
• rs1486519695
• NM_178563.4:c.2396C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178563.4(AGBL3):​c.2396C>T​(p.Ala799Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,398,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: AGBL3 NM_178563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.451
• Publications: 0 publications found

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: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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05018595).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178563.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL3	NM_178563.4	MANE Select	c.2396C>T	p.Ala799Val	missense	Exon 17 of 17	NP_848658.3	Q8NEM8-4
	AGBL3	NM_001345850.1		c.899C>T	p.Ala300Val	missense	Exon 12 of 12	NP_001332779.1
	AGBL3	NM_001345851.1		c.719C>T	p.Ala240Val	missense	Exon 11 of 11	NP_001332780.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL3	ENST00000436302.6	TSL:2 MANE Select	c.2396C>T	p.Ala799Val	missense	Exon 17 of 17	ENSP00000388275.2	Q8NEM8-4
	CYREN	ENST00000459937.5	TSL:1	n.356+33855G>A		intron	N/A
	AGBL3	ENST00000435976.6	TSL:5	c.2111-12919C>T		intron	N/A	ENSP00000401220.2	F8W7R4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1398962 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4 AN XY: 690012

African (AFR) AF: 0.00 AC: 0 AN: 31570

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078640

Other (OTH) AF: 0.00 AC: 0 AN: 57982

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.45
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.0090
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.80	T
Polyphen		0.0070	B
Vest4		0.092
MutPred		0.19		Gain of MoRF binding (P = 0.1117)
MVP		0.014
ClinPred		0.20	T
GERP RS		2.3
gMVP		0.056
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1486519695; hg19: chr7-134819646; COSMIC: COSV104714439;