Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001386094.1(AGBL1):c.3044G>C(p.Cys1015Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,612,102 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 4 hom. )

Consequence

AGBL1
NM_001386094.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 5.91

Publications

15 publications found

Variant links:

Genes affected

AGBL1 (HGNC:26504): (AGBL carboxypeptidase 1) Polyglutamylation is a reversible posttranslational modification catalyzed by polyglutamylases that results in the addition of glutamate side chains on the modified protein. This gene encodes a glutamate decarboxylase that catalyzes the deglutamylation of polyglutamylated proteins. Mutations in this gene result in dominant late-onset Fuchs corneal dystrophy. [provided by RefSeq, Nov 2013]

AGBL1 Gene-Disease associations (from GenCC):

Fuchs' endothelial dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
corneal dystrophy, Fuchs endothelial, 8
Inheritance: AD Classification: LIMITED Submitted by: G2P

AGBL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020041704).

BP6

Variant 15-86674322-G-C is Benign according to our data. Variant chr15-86674322-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 88758.

BS2

High AC in GnomAd4 at 198 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386094.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL1	NM_001386094.1	MANE Select	c.3044G>C	p.Cys1015Ser	missense	Exon 22 of 23	NP_001373023.1
	AGBL1	NM_152336.4		c.3107G>C	p.Cys1036Ser	missense	Exon 23 of 25	NP_689549.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGBL1	ENST00000614907.3	TSL:5 MANE Select	c.3044G>C	p.Cys1015Ser	missense	Exon 22 of 23	ENSP00000490608.2
AGBL1	ENST00000441037.7	TSL:5	c.3107G>C	p.Cys1036Ser	missense	Exon 23 of 25	ENSP00000413001.3
AGBL1	ENST00000681381.1		n.203G>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00119

AC:

291

AN:

244704

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.000400

Gnomad AMR exome

AF:

0.000557

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.000672

GnomAD4 exome

AF:

0.00202

AC:

2949

AN:

1459780

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1453

AN XY:

725926

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33448

American (AMR)

AF:

0.000584

AC:

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

85812

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00242

AC:

2687

AN:

1111044

Other (OTH)

AF:

0.00181

AC:

109

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

153

306

458

611

764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00130

AC:

198

AN:

152322

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41564

American (AMR)

AF:

0.00105

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68036

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00198

Hom.:

Bravo

AF:

0.00130

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000500

AC:

ESP6500EA

AF:

0.00252

AC:

ExAC

AF:

0.00126

AC:

152

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Corneal dystrophy, Fuchs endothelial, 8 (3)

Fuchs' endothelial dystrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

PhyloP100

5.9

PrimateAI

Uncertain

0.53

Polyphen

1.0

MutPred

0.76

Gain of disorder (P = 0.0257)

MVP

0.31

MPC

0.049

ClinPred

0.11

GERP RS

5.5

Varity_R

0.38

gMVP

0.60

Mutation Taster

=98/2

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over