X-57286924-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_174912.4(FAAH2):c.99T>C(p.Gly33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,201,299 control chromosomes in the GnomAD database, including 45,773 homozygotes. There are 111,397 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (11426 hom., 13405 hem., cov: 21)
  • Exomes 𝑓: 0.27 (34347 hom. 97992 hem.)
• Consequence: FAAH2 NM_174912.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.539

Genes affected

FAAH2 (HGNC:26440): (fatty acid amide hydrolase 2) This gene encodes a fatty acid amide hydrolase that shares a conserved protein motif with the amidase signature family of enzymes. The encoded enzyme is able to catalyze the hydrolysis of a broad range of bioactive lipids, including those from the three main classes of fatty acid amides; N-acylethanolamines, fatty acid primary amides and N-acyl amino acids. This enzyme has a preference for monounsaturated acyl chains as a substrate. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-57286924-T-C is Benign according to our data. Variant chrX-57286924-T-C is described in ClinVar as [Benign]. Clinvar id is 3056042.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-57286924-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.539 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.99T>C	p.Gly33=	synonymous_variant	1/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.99T>C	p.Gly33=	synonymous_variant	1/11	1	NM_174912.4	P1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 49239 AN: 108937 Hom.: 11414 Cov.: 21 AF XY: 0.426 AC XY: 13345 AN XY: 31303

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.0996

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.502

GnomAD3 exomes AF: 0.353 AC: 61289 AN: 173775 Hom.: 9996 AF XY: 0.324 AC XY: 19122 AN XY: 59067

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.274 AC: 299744 AN: 1092309 Hom.: 34347 Cov.: 32 AF XY: 0.273 AC XY: 97992 AN XY: 358655

Gnomad4 AFR exome AF: 0.911

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.347

GnomAD4 genome AF: 0.452 AC: 49314 AN: 108990 Hom.: 11426 Cov.: 21 AF XY: 0.427 AC XY: 13405 AN XY: 31366

Gnomad4 AFR AF: 0.888

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.466

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.510

Alfa AF: 0.355 Hom.: 9132

Bravo AF: 0.500

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FAAH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2020

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	-0.97
Cadd	Benign	3.0
Dann	Benign	0.38

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: rs2516023; hg19: chrX-57313357; COSMIC: COSV66506210;