X-57341373-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_174912.4(FAAH2):c.725G>C(p.Gly242Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FAAH2 NM_174912.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.725G>C	p.Gly242Ala	missense_variant	5/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.725G>C	p.Gly242Ala	missense_variant	5/11	1	NM_174912.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

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

May 25, 2022

The c.725G>C (p.G242A) alteration is located in exon 5 (coding exon 5) of the FAAH2 gene. This alteration results from a G to C substitution at nucleotide position 725, causing the glycine (G) at amino acid position 242 to be replaced by an alanine (A). 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	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.97		Gain of catalytic residue at G242 (P = 0.0198);
MVP		0.68
MPC		0.0013
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs935963549; hg19: chrX-57367806;