rs10520618

Variant names:

• chr15-86264530-A-G
• rs10520618
• NM_001386094.1:c.1359A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001386094.1(AGBL1):​c.1359A>G​(p.Glu453Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,684 control chromosomes in the GnomAD database, including 149,103 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (18798 hom., cov: 32)
  • Exomes 𝑓: 0.42 (130305 hom.)
• Consequence: AGBL1 NM_001386094.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=2.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGBL1	NM_001386094.1	c.1359A>G	p.Glu453Glu	synonymous_variant	Exon 11 of 23	ENST00000614907.3	NP_001373023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGBL1	ENST00000614907.3	c.1359A>G	p.Glu453Glu	synonymous_variant	Exon 11 of 23	5	NM_001386094.1	ENSP00000490608.2
AGBL1	ENST00000568785.5	n.543A>G		non_coding_transcript_exon_variant	Exon 2 of 8	1
AGBL1	ENST00000441037.7	c.1359A>G	p.Glu453Glu	synonymous_variant	Exon 11 of 25	5		ENSP00000413001.3
AGBL1	ENST00000567715.1	n.433A>G		non_coding_transcript_exon_variant	Exon 3 of 9	2

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73828 AN: 151988 Hom.: 18772 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.491

GnomAD2 exomes AF: 0.435 AC: 108425 AN: 248984 AF XY: 0.437

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.418 AC: 611605 AN: 1461578 Hom.: 130305 Cov.: 72 AF XY: 0.421 AC XY: 306079 AN XY: 727056

African (AFR) AF: 0.650 AC: 21749 AN: 33476

American (AMR) AF: 0.416 AC: 18611 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 12901 AN: 26128

East Asian (EAS) AF: 0.353 AC: 14026 AN: 39700

South Asian (SAS) AF: 0.495 AC: 42717 AN: 86238

European-Finnish (FIN) AF: 0.380 AC: 20271 AN: 53386

Middle Eastern (MID) AF: 0.517 AC: 2981 AN: 5768

European-Non Finnish (NFE) AF: 0.406 AC: 451223 AN: 1111794

Other (OTH) AF: 0.449 AC: 27126 AN: 60372

GnomAD4 genome AF: 0.486 AC: 73901 AN: 152106 Hom.: 18798 Cov.: 32 AF XY: 0.482 AC XY: 35850 AN XY: 74352

African (AFR) AF: 0.637 AC: 26449 AN: 41494

American (AMR) AF: 0.467 AC: 7144 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3468

East Asian (EAS) AF: 0.365 AC: 1893 AN: 5182

South Asian (SAS) AF: 0.497 AC: 2394 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4016 AN: 10580

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.423 AC: 28761 AN: 67964

Other (OTH) AF: 0.489 AC: 1031 AN: 2110

Alfa AF: 0.446 Hom.: 27363

Bravo AF: 0.495

Asia WGS AF: 0.463 AC: 1614 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10520618; hg19: chr15-86807761; COSMIC: COSV66850936;