20-25300304-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.*541G>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 0.00364 in 1,028,370 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: ABHD12 NM_001042472.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92

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=-0.88).
• BP6: Variant 20-25300304-C-T is Benign according to our data. Variant chr20-25300304-C-T is described in ClinVar as [Benign]. Clinvar id is 897013.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.007 (1065/152070) while in subpopulation AFR AF= 0.0176 (728/41464). AF 95% confidence interval is 0.0165. There are 5 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD12	NM_001042472.3	c.*541G>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.*541G>A		3_prime_UTR_variant	13/13	2	NM_001042472.3	P1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1065 AN: 151952 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00306 AC: 2681 AN: 876300 Hom.: 8 Cov.: 28 AF XY: 0.00306 AC XY: 1244 AN XY: 406758

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.00737

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00410

GnomAD4 genome AF: 0.00700 AC: 1065 AN: 152070 Hom.: 5 Cov.: 31 AF XY: 0.00634 AC XY: 471 AN XY: 74330

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00790

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PHARC syndrome Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.17
Dann	Benign	0.48
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: rs41304802; hg19: chr20-25280940;