chr2-27054035-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_021831.6(AGBL5):​c.527C>T​(p.Pro176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

AGBL5
NM_021831.6 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.296
Variant links:
Genes affected
AGBL5 (HGNC:26147): (AGBL carboxypeptidase 5) This gene encodes a metallocarboxypeptidase involved in protein deglutamylation and a member of the peptidase M14 family of proteins. The encoded protein has been described as a "dual-functional" deglutamylase that can remove glutamate residues from both carboxyl termini and side chains of protein substrates. This deglutamylase activity may be important in antiviral immunity. Mutations in this gene are associated with retinitis pigmentosa. [provided by RefSeq, Jul 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010996193).
BP6
Variant 2-27054035-C-T is Benign according to our data. Variant chr2-27054035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 871081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000151 (23/152320) while in subpopulation SAS AF= 0.000415 (2/4824). AF 95% confidence interval is 0.000159. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGBL5NM_021831.6 linkc.527C>T p.Pro176Leu missense_variant Exon 4 of 15 ENST00000360131.5 NP_068603.4 Q8NDL9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGBL5ENST00000360131.5 linkc.527C>T p.Pro176Leu missense_variant Exon 4 of 15 1 NM_021831.6 ENSP00000353249.4 Q8NDL9-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000171
AC:
43
AN:
250892
Hom.:
0
AF XY:
0.000170
AC XY:
23
AN XY:
135578
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000255
AC:
373
AN:
1461430
Hom.:
0
Cov.:
31
AF XY:
0.000231
AC XY:
168
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000293
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000218
Hom.:
0
Bravo
AF:
0.000162
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000165
AC:
20
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 176 of the AGBL5 protein (p.Pro176Leu). This variant is present in population databases (rs142859717, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AGBL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 871081). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Nov 05, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
12
DANN
Benign
0.67
DEOGEN2
Benign
0.032
.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.64
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.045
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.039
Sift
Benign
0.47
T;.
Sift4G
Benign
0.36
T;T
Polyphen
0.0
B;B
Vest4
0.063
MVP
0.13
MPC
0.58
ClinPred
0.013
T
GERP RS
-1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.17
gMVP
0.36

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: rs142859717; hg19: chr2-27276903; API