1-48587118-G-C

Variant names:

• chr1-48587118-G-C
• rs555192599
• NM_032785.4:c.1153C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032785.4(AGBL4):​c.1153C>G​(p.Arg385Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AGBL4 NM_032785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

AGBL4 (HGNC:25892): (AGBL carboxypeptidase 4) Predicted to enable metallocarboxypeptidase activity and tubulin binding activity. Predicted to be involved in C-terminal protein deglutamylation; defense response to virus; and protein side chain deglutamylation. Predicted to act upstream of or within several processes, including axonal transport of mitochondrion; positive regulation of ubiquitin-dependent protein catabolic process; and regulation of blastocyst development. Located in Golgi apparatus; centriole; and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032785.4. 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
	AGBL4	NM_032785.4	MANE Select	c.1153C>G	p.Arg385Gly	missense	Exon 11 of 14	NP_116174.3	Q5VU57-1
	AGBL4	NM_001323574.2		c.1189C>G	p.Arg397Gly	missense	Exon 11 of 14	NP_001310503.1
	AGBL4	NM_001323573.2		c.1189C>G	p.Arg397Gly	missense	Exon 11 of 13	NP_001310502.1	Q5VU57-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL4	ENST00000371839.6	TSL:2 MANE Select	c.1153C>G	p.Arg385Gly	missense	Exon 11 of 14	ENSP00000360905.1	Q5VU57-1
	AGBL4	ENST00000416121.5	TSL:1	c.688C>G	p.Arg230Gly	missense	Exon 7 of 7	ENSP00000401622.1	H0Y5X4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419458 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 701942

African (AFR) AF: 0.00 AC: 0 AN: 32490

American (AMR) AF: 0.00 AC: 0 AN: 37546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25344

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37302

South Asian (SAS) AF: 0.00 AC: 0 AN: 80592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090648

Other (OTH) AF: 0.00 AC: 0 AN: 58958

GnomAD4 genome Cov.: 31

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.62		Loss of methylation at R385 (P = 0.0195)
MVP		0.32
MPC		0.67
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.81
Mutation Taster		=50/50

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: rs555192599; hg19: chr1-49052790;