chr1-48590895-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032785.4(AGBL4):​c.1042C>T​(p.Arg348Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,608,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

AGBL4
NM_032785.4 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3485186).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AGBL4NM_032785.4 linkuse as main transcriptc.1042C>T p.Arg348Trp missense_variant 10/14 ENST00000371839.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AGBL4ENST00000371839.6 linkuse as main transcriptc.1042C>T p.Arg348Trp missense_variant 10/142 NM_032785.4 P1Q5VU57-1
AGBL4ENST00000416121.5 linkuse as main transcriptc.580C>T p.Arg194Trp missense_variant 6/71

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152040
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000375
AC:
9
AN:
240192
Hom.:
0
AF XY:
0.0000154
AC XY:
2
AN XY:
129834
show subpopulations
Gnomad AFR exome
AF:
0.000342
Gnomad AMR exome
AF:
0.0000297
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000275
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1456294
Hom.:
0
Cov.:
31
AF XY:
0.0000111
AC XY:
8
AN XY:
723566
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152040
Hom.:
0
Cov.:
31
AF XY:
0.0000539
AC XY:
4
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.000242
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000511
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000497
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2023The c.1042C>T (p.R348W) alteration is located in exon 10 (coding exon 10) of the AGBL4 gene. This alteration results from a C to T substitution at nucleotide position 1042, causing the arginine (R) at amino acid position 348 to be replaced by a tryptophan (W). 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
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.075
T;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.35
T;T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Pathogenic
3.1
M;.
MutationTaster
Benign
0.90
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.5
D;.
REVEL
Benign
0.28
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.56
MVP
0.16
MPC
0.61
ClinPred
0.83
D
GERP RS
2.7
Varity_R
0.69
gMVP
0.68

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376731078; hg19: chr1-49056567; API