X-57286949-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_174912.4(FAAH2):c.124C>T(p.Arg42Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0086 in 1,200,848 control chromosomes in the GnomAD database, including 36 homozygotes. There are 3,267 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., 176 hem., cov: 21)
  • Exomes 𝑓: 0.0088 (32 hom. 3091 hem.)
• Consequence: FAAH2 NM_174912.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.808

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004681617).
• BP6: Variant X-57286949-C-T is Benign according to our data. Variant chrX-57286949-C-T is described in ClinVar as [Benign]. Clinvar id is 771788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.124C>T	p.Arg42Trp	missense_variant	1/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.124C>T	p.Arg42Trp	missense_variant	1/11	1	NM_174912.4	P1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 708 AN: 110618 Hom.: 5 Cov.: 21 AF XY: 0.00536 AC XY: 176 AN XY: 32818

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.00442

Gnomad ASJ AF: 0.0174

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00195

Gnomad FIN AF: 0.00410

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.00747

GnomAD3 exomes AF: 0.00715 AC: 1228 AN: 171787 Hom.: 3 AF XY: 0.00674 AC XY: 386 AN XY: 57279

Gnomad AFR exome AF: 0.00147

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00198

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00858

GnomAD4 exome AF: 0.00883 AC: 9625 AN: 1090177 Hom.: 32 Cov.: 31 AF XY: 0.00867 AC XY: 3091 AN XY: 356459

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00612

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.00636 AC: 704 AN: 110671 Hom.: 4 Cov.: 21 AF XY: 0.00535 AC XY: 176 AN XY: 32881

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00442

Gnomad4 ASJ AF: 0.0174

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00195

Gnomad4 FIN AF: 0.00410

Gnomad4 NFE AF: 0.00998

Gnomad4 OTH AF: 0.00737

Alfa AF: 0.0105 Hom.: 478

Bravo AF: 0.00638

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0111 AC: 32

ESP6500AA AF: 0.00156 AC: 6

ESP6500EA AF: 0.0113 AC: 76

ExAC AF: 0.00772 AC: 937

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.020	D
Polyphen		0.93	P
Vest4		0.086
MVP		0.38
MPC		0.0011
ClinPred		0.035	T
GERP RS		-0.58
Varity_R		0.080
gMVP		0.43

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: rs146874627; hg19: chrX-57313382; COSMIC: COSV105316067;