rs1046073

Positions:

• chr20-25300697-G-A
• chr20-25300697-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042472.3(ABHD12):​c.*148C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,542,216 control chromosomes in the GnomAD database, including 162,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16018 hom., cov: 33)
  • Exomes 𝑓: 0.45 (146204 hom.)
• Consequence: ABHD12 NM_001042472.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.21

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 20-25300697-G-A is Benign according to our data. Variant chr20-25300697-G-A is described in ClinVar as [Benign]. Clinvar id is 337987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABHD12	NM_001042472.3	c.*148C>T		3_prime_UTR_variant	13/13	ENST00000339157.10	NP_001035937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABHD12	ENST00000339157.10	c.*148C>T		3_prime_UTR_variant	13/13	2	NM_001042472.3	ENSP00000341408	P1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68379 AN: 151924 Hom.: 16009 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.450 AC: 625796 AN: 1390174 Hom.: 146204 Cov.: 41 AF XY: 0.450 AC XY: 308931 AN XY: 686086

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.916

Gnomad4 SAS exome AF: 0.461

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.441

Gnomad4 OTH exome AF: 0.458

GnomAD4 genome AF: 0.450 AC: 68421 AN: 152042 Hom.: 16018 Cov.: 33 AF XY: 0.452 AC XY: 33563 AN XY: 74320

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.918

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.443

Gnomad4 OTH AF: 0.424

Alfa AF: 0.428 Hom.: 4553

Bravo AF: 0.445

Asia WGS AF: 0.679 AC: 2359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.94
CADD	Benign	0.071
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1046073; hg19: chr20-25281333;