Genetic Variant NM_178563.4:c.208C>T (chr7-134993576-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_178563.4(AGBL3):c.208C>T(p.Arg70Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,551,844 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 73 hom. )

Consequence

AGBL3
NM_178563.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.03

Publications

7 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010233521).

BP6

Variant 7-134993576-C-T is Benign according to our data. Variant chr7-134993576-C-T is described in ClinVar as Benign. ClinVar VariationId is 783007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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.208C>T	p.Arg70Cys	missense	Exon 4 of 17	NP_848658.3	Q8NEM8-4
AGBL3	NM_001345851.1		c.-208C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001332780.1
AGBL3	NM_001367812.1		c.208C>T	p.Arg70Cys	missense	Exon 4 of 5	NP_001354741.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGBL3	ENST00000436302.6	TSL:2 MANE Select	c.208C>T	p.Arg70Cys	missense	Exon 4 of 17	ENSP00000388275.2	Q8NEM8-4
AGBL3	ENST00000275763.10	TSL:1	n.208C>T		non_coding_transcript_exon	Exon 4 of 17	ENSP00000275763.6	Q8NEM8-2
AGBL3	ENST00000435976.6	TSL:5	c.208C>T	p.Arg70Cys	missense	Exon 4 of 16	ENSP00000401220.2	F8W7R4

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

948

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00774

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00533

AC:

842

AN:

158014

AF XY:

0.00532

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.000971

Gnomad ASJ exome

AF:

0.000234

Gnomad EAS exome

AF:

0.000275

Gnomad FIN exome

AF:

0.00768

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00880

AC:

12323

AN:

1399612

Hom.:

Cov.:

AF XY:

0.00854

AC XY:

5896

AN XY:

690292

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

31594

American (AMR)

AF:

0.00120

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000238

AC:

AN:

25180

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35730

South Asian (SAS)

AF:

0.00109

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00757

AC:

374

AN:

49388

Middle Eastern (MID)

AF:

0.000526

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0106

AC:

11421

AN:

1078972

Other (OTH)

AF:

0.00585

AC:

340

AN:

58108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

620

1240

1860

2480

3100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

430

860

1290

1720

2150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00623

AC:

948

AN:

152232

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

443

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41538

American (AMR)

AF:

0.00118

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00774

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

751

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00835

Hom.:

Bravo

AF:

0.00544

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00880

AC:

ExAC

AF:

0.00410

AC:

105

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.011

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.50

MVP

0.36

ClinPred

0.036

GERP RS

4.9

gMVP

0.62

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over