20-25300391-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001042472.3(ABHD12):c.*454G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,122,144 control chromosomes in the GnomAD database, including 579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (66 hom., cov: 31)
  • Exomes 𝑓: 0.032 (513 hom.)
• Consequence: ABHD12 NM_001042472.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85

Genes affected

ABHD12 (HGNC:15868): (abhydrolase domain containing 12, lysophospholipase) This gene encodes an enzyme that catalyzes the hydrolysis of 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors, CB1 and CB2. The endocannabinoid system is involved in a wide range of physiological processes, including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation. Mutations in this gene are associated with the neurodegenerative disease, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), resulting from an inborn error of endocannabinoid metabolism. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-25300391-C-T is Benign according to our data. Variant chr20-25300391-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 337980.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-25300391-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0272 (4122/151732) while in subpopulation AMR AF= 0.05 (763/15246). AF 95% confidence interval is 0.0471. There are 66 homozygotes in gnomad4. There are 2127 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD12	NM_001042472.3	c.*454G>A		3_prime_UTR_variant	13/13	ENST00000339157.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD12	ENST00000339157.10	c.*454G>A		3_prime_UTR_variant	13/13	2	NM_001042472.3	P1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4116 AN: 151616 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.0312

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0340

GnomAD4 exome AF: 0.0318 AC: 30873 AN: 970412 Hom.: 513 Cov.: 28 AF XY: 0.0320 AC XY: 14621 AN XY: 457474

Gnomad4 AFR exome AF: 0.00401

Gnomad4 AMR exome AF: 0.0435

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.000283

Gnomad4 SAS exome AF: 0.0335

Gnomad4 FIN exome AF: 0.0439

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0272 AC: 4122 AN: 151732 Hom.: 66 Cov.: 31 AF XY: 0.0287 AC XY: 2127 AN XY: 74138

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0500

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00254

Gnomad4 SAS AF: 0.0314

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0337

Alfa AF: 0.0302 Hom.: 17

Bravo AF: 0.0266

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PHARC syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.083
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs41309917; hg19: chr20-25281027;