Genetic Variant NM_178563.4:c.362C>A (chr7-135017103-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178563.4(AGBL3):c.362C>A(p.Thr121Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T121M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGBL3
NM_178563.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.305

Publications

2 publications found

Variant links:

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]

AGBL3 links:

ENSG00000286458 (HGNC:):

ENSG00000286458 links:

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ACMG classification

Classification was made for transcript

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=0.044008523).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGBL3	NM_178563.4	MANE Select	c.362C>A	p.Thr121Lys	missense	Exon 5 of 17	NP_848658.3	Q8NEM8-4
AGBL3	NM_001345850.1		c.-54C>A		5_prime_UTR	Exon 3 of 12	NP_001332779.1
AGBL3	NM_001345851.1		c.-54C>A		5_prime_UTR	Exon 4 of 11	NP_001332780.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGBL3	ENST00000436302.6	TSL:2 MANE Select	c.362C>A	p.Thr121Lys	missense	Exon 5 of 17	ENSP00000388275.2	Q8NEM8-4
AGBL3	ENST00000275763.10	TSL:1	n.362C>A		non_coding_transcript_exon	Exon 5 of 17	ENSP00000275763.6	Q8NEM8-2
AGBL3	ENST00000435976.6	TSL:5	c.362C>A	p.Thr121Lys	missense	Exon 5 of 16	ENSP00000401220.2	F8W7R4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1399096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690070

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35694

South Asian (SAS)

AF:

0.00

AC:

AN:

79210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078370

Other (OTH)

AF:

0.00

AC:

AN:

58146

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.082

(source)

DANN

Benign

0.41

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.12

M_CAP

Benign

0.0045

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.76

PhyloP100

-0.30

PrimateAI

Benign

0.28

PROVEAN

Benign

1.8

REVEL

Benign

0.046

Sift

Benign

0.46

Sift4G

Benign

0.60

Polyphen

0.0030

Vest4

0.15

MutPred

0.42

Gain of ubiquitination at T121 (P = 0.0054)

MVP

0.014

ClinPred

0.18

GERP RS

-1.9

gMVP

0.22

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over