chr2-27053019-C-T

Variant names:

• chr2-27053019-C-T
• NM_021831.6:c.61C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021831.6(AGBL5):​c.61C>T​(p.His21Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H21H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGBL5 NM_021831.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

AGBL5 (HGNC:26147): (AGBL carboxypeptidase 5) This gene encodes a metallocarboxypeptidase involved in protein deglutamylation and a member of the peptidase M14 family of proteins. The encoded protein has been described as a "dual-functional" deglutamylase that can remove glutamate residues from both carboxyl termini and side chains of protein substrates. This deglutamylase activity may be important in antiviral immunity. Mutations in this gene are associated with retinitis pigmentosa. [provided by RefSeq, Jul 2016]

AGBL5 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 75

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33080232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021831.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL5	NM_021831.6	MANE Select	c.61C>T	p.His21Tyr	missense	Exon 2 of 15	NP_068603.4
	AGBL5	NM_001035507.3		c.61C>T	p.His21Tyr	missense	Exon 2 of 11	NP_001030584.1	Q8NDL9-3
	AGBL5	NR_104246.2		n.233C>T		non_coding_transcript_exon	Exon 2 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL5	ENST00000360131.5	TSL:1 MANE Select	c.61C>T	p.His21Tyr	missense	Exon 2 of 15	ENSP00000353249.4	Q8NDL9-1
	AGBL5	ENST00000323064.12	TSL:1	c.61C>T	p.His21Tyr	missense	Exon 2 of 11	ENSP00000323681.8	Q8NDL9-3
	AGBL5	ENST00000487078.5	TSL:1	n.61C>T		non_coding_transcript_exon	Exon 2 of 16	ENSP00000433830.1	Q8NDL9-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461404 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.33		Loss of disorder (P = 0.0357)
MVP		0.63
MPC		0.76
ClinPred		0.93	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.60
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr2-27275887;