1-48539679-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032785.4(AGBL4):c.1327G>A(p.Val443Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,543,826 control chromosomes in the GnomAD database, including 1,587 homozygotes. 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.059 (873 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (714 hom.)
• Consequence: AGBL4 NM_032785.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.00

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031241477).
• BP6: Variant 1-48539679-C-T is Benign according to our data. Variant chr1-48539679-C-T is described in ClinVar as [Benign]. Clinvar id is 3056820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL4	NM_032785.4	c.1327G>A	p.Val443Met	missense_variant	12/14	ENST00000371839.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL4	ENST00000371839.6	c.1327G>A	p.Val443Met	missense_variant	12/14	2	NM_032785.4	P1

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8980 AN: 152024 Hom.: 872 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0118 AC: 1817 AN: 153414 Hom.: 146 AF XY: 0.00941 AC XY: 763 AN XY: 81110

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000904

Gnomad OTH exome AF: 0.00727

GnomAD4 exome AF: 0.00598 AC: 8319 AN: 1391684 Hom.: 714 Cov.: 30 AF XY: 0.00513 AC XY: 3517 AN XY: 685878

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000460

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000522

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0591 AC: 8991 AN: 152142 Hom.: 873 Cov.: 32 AF XY: 0.0563 AC XY: 4191 AN XY: 74398

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0108 Hom.: 221

Bravo AF: 0.0677

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.207 AC: 287

ESP6500EA AF: 0.00126 AC: 4

ExAC AF: 0.0213 AC: 544

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AGBL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.61
Dann	Benign	0.75
DEOGEN2	Benign	0.0050	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.018
Sift	Benign	0.31	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.037	B;.
Vest4		0.027
MPC		0.13
ClinPred		0.0036	T
GERP RS		-2.2
Varity_R		0.031
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs60977321; hg19: chr1-49005351; COSMIC: COSV61893985;