X-57331631-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_174912.4(FAAH2):c.446G>A(p.Arg149His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,209,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000036 (0 hom. 21 hem.)
• Consequence: FAAH2 NM_174912.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29708582).
• BS2: High Hemizygotes in GnomAdExome at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.446G>A	p.Arg149His	missense_variant	4/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.446G>A	p.Arg149His	missense_variant	4/11	1	NM_174912.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000717 AC: 8 AN: 111653 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33859

Gnomad AFR AF: 0.0000977

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.0000601 AC: 11 AN: 182997 Hom.: 0 AF XY: 0.0000888 AC XY: 6 AN XY: 67605

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000355 AC: 39 AN: 1097913 Hom.: 0 Cov.: 30 AF XY: 0.0000578 AC XY: 21 AN XY: 363319

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000717 AC: 8 AN: 111653 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33859

Gnomad4 AFR AF: 0.0000977

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.000667

Bravo AF: 0.0000302

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.446G>A (p.R149H) alteration is located in exon 4 (coding exon 4) of the FAAH2 gene. This alteration results from a G to A substitution at nucleotide position 446, causing the arginine (R) at amino acid position 149 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.13
MutPred		0.61		Loss of methylation at R149 (P = 0.0308);
MVP		0.67
MPC		0.0011
ClinPred		0.54	D
GERP RS		2.4
Varity_R		0.24
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs773977954; hg19: chrX-57358064;