rs147173444

chrX-57448667-G-AchrX-57448667-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_174912.4(FAAH2):c.1372G>A(p.Ala458Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000794 in 1,209,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A458S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000077 (0 hom. 27 hem.)
• Consequence: FAAH2 NM_174912.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50

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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.1372G>A	p.Ala458Thr	missense_variant	10/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.1372G>A	p.Ala458Thr	missense_variant	10/11	1	NM_174912.4	P1
FAAH2	ENST00000491179.1	n.51-15G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
FAAH2	ENST00000465623.1	n.296G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 11 AN: 111654 Hom.: 0 Cov.: 23 AF XY: 0.0000591 AC XY: 2 AN XY: 33848

Gnomad AFR AF: 0.000293

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 8 AN: 182549 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67083

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000774 AC: 85 AN: 1097698 Hom.: 0 Cov.: 32 AF XY: 0.0000744 AC XY: 27 AN XY: 363124

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000915

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000985 AC: 11 AN: 111654 Hom.: 0 Cov.: 23 AF XY: 0.0000591 AC XY: 2 AN XY: 33848

Gnomad4 AFR AF: 0.000293

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000110

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000741 AC: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.68
MPC		0.0016
ClinPred		0.86	D
GERP RS		2.5
Varity_R		0.74
gMVP		0.78

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: rs147173444; hg19: chrX-57475100;