1-48653455-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_032785.4(AGBL4):c.725-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,558,102 control chromosomes in the GnomAD database, including 575 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (64 hom., cov: 32)
  • Exomes 𝑓: 0.025 (511 hom.)
• Consequence: AGBL4 NM_032785.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.03904
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37

Genes affected

AGBL4 (HGNC:25892): (AGBL carboxypeptidase 4) Predicted to enable metallocarboxypeptidase activity and tubulin binding activity. Predicted to be involved in C-terminal protein deglutamylation; defense response to virus; and protein side chain deglutamylation. Predicted to act upstream of or within several processes, including axonal transport of mitochondrion; positive regulation of ubiquitin-dependent protein catabolic process; and regulation of blastocyst development. Located in Golgi apparatus; centriole; and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-48653455-G-A is Benign according to our data. Variant chr1-48653455-G-A is described in ClinVar as [Benign]. Clinvar id is 3055503.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0272 (4144/152260) while in subpopulation SAS AF= 0.0506 (244/4824). AF 95% confidence interval is 0.0454. There are 64 homozygotes in gnomad4. There are 2007 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL4	NM_032785.4	c.725-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371839.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL4	ENST00000371839.6	c.725-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_032785.4	P1
AGBL4	ENST00000416121.5	c.262-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
AGBL4	ENST00000371838.5	c.725-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4137 AN: 152142 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0291

GnomAD3 exomes AF: 0.0250 AC: 4358 AN: 173974 Hom.: 65 AF XY: 0.0269 AC XY: 2470 AN XY: 91986

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.000399

Gnomad SAS exome AF: 0.0517

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0254 AC: 35720 AN: 1405842 Hom.: 511 Cov.: 27 AF XY: 0.0259 AC XY: 18025 AN XY: 695332

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.000161

Gnomad4 SAS exome AF: 0.0471

Gnomad4 FIN exome AF: 0.0241

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0272 AC: 4144 AN: 152260 Hom.: 64 Cov.: 32 AF XY: 0.0270 AC XY: 2007 AN XY: 74452

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.0264

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0206 Hom.: 25

Bravo AF: 0.0253

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AGBL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	13
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.039
dbscSNV1_RF	Benign	0.22
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

LitVar

Other links and lift over

dbSNP: rs41289226; hg19: chr1-49119127;