Genetic Variant AGBL3:c.2343-9C>A (chr7-135134832-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4BP6_ModerateBS1BS2

The NM_178563.4(AGBL3):c.2343-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,546,538 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0070 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 13 hom. )

Consequence

AGBL3
NM_178563.4 intron

Scores

Splicing: ADA: 0.2887

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.27

Publications

0 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:

CYREN (HGNC:22432): (cell cycle regulator of NHEJ) Involved in double-strand break repair via nonhomologous end joining and negative regulation of double-strand break repair via nonhomologous end joining. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CYREN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.16).

BP6

Variant 7-135134832-C-A is Benign according to our data. Variant chr7-135134832-C-A is described in ClinVar as Benign. ClinVar VariationId is 788544.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.007 (1065/152184) while in subpopulation AFR AF = 0.0244 (1015/41544). AF 95% confidence interval is 0.0232. There are 14 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 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	Effect	Exon Rank	Protein	UniProt
AGBL3	NM_178563.4	MANE Select	c.2343-9C>A	intron	N/A	NP_848658.3	Q8NEM8-4
AGBL3	NM_001345850.1		c.846-9C>A	intron	N/A	NP_001332779.1
AGBL3	NM_001345851.1		c.666-9C>A	intron	N/A	NP_001332780.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AGBL3	ENST00000436302.6	TSL:2 MANE Select	c.2343-9C>A	intron	N/A	ENSP00000388275.2	Q8NEM8-4
CYREN	ENST00000459937.5	TSL:1	n.356+33917G>T	intron	N/A
AGBL3	ENST00000435976.6	TSL:5	c.2111-12981C>A	intron	N/A	ENSP00000401220.2	F8W7R4

Frequencies

GnomAD3 genomes

AF:

0.00701

AC:

1066

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00243

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:

0.0000882

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00138

AC:

208

AN:

151104

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.000823

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000708

GnomAD4 exome

AF:

0.000602

AC:

839

AN:

1394354

Hom.:

Cov.:

AF XY:

0.000492

AC XY:

338

AN XY:

687240

show subpopulations

African (AFR)

AF:

0.0232

AC:

727

AN:

31336

American (AMR)

AF:

0.00108

AC:

AN:

35270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24928

East Asian (EAS)

AF:

0.00

AC:

AN:

35680

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00000372

AC:

AN:

1075644

Other (OTH)

AF:

0.00119

AC:

AN:

57758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00700

AC:

1065

AN:

152184

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0244

AC:

1015

AN:

41544

American (AMR)

AF:

0.00242

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67990

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

153

204

255

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:

0.00237

Hom.:

Bravo

AF:

0.00825

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.29

dbscSNV1_RF

Benign

0.39

SpliceAI score (max)

0.020

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