Genetic Variant FAAH2:p.Ala458Ser (chrX-57448667-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174912.4(FAAH2):c.1372G>T(p.Ala458Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,209,408 control chromosomes in the GnomAD database, including 2 homozygotes. There are 101 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00028 ( 2 hom. 96 hem. )

Consequence

FAAH2
NM_174912.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.50

Publications

5 publications found

Variant links:

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]

FAAH2 Gene-Disease associations (from GenCC):

X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

FAAH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09746036).

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174912.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAAH2	NM_174912.4	MANE Select	c.1372G>T	p.Ala458Ser	missense	Exon 10 of 11	NP_777572.2	Q6GMR7
FAAH2	NM_001353840.1		c.1252G>T	p.Ala418Ser	missense	Exon 9 of 10	NP_001340769.1
FAAH2	NM_001353841.1		c.1162G>T	p.Ala388Ser	missense	Exon 9 of 10	NP_001340770.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAAH2	ENST00000374900.5	TSL:1 MANE Select	c.1372G>T	p.Ala458Ser	missense	Exon 10 of 11	ENSP00000364035.4	Q6GMR7
FAAH2	ENST00000491179.1	TSL:1	n.51-15G>T		intron	N/A
FAAH2	ENST00000886040.1		c.1399G>T	p.Ala467Ser	missense	Exon 11 of 12	ENSP00000556099.1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111654

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000381

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:

0.000207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000509

AC:

AN:

182549

AF XY:

0.000432

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad FIN exome

AF:

0.000313

Gnomad NFE exome

AF:

0.000981

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000284

AC:

312

AN:

1097697

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

363123

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26388

American (AMR)

AF:

0.000171

AC:

AN:

35146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30183

South Asian (SAS)

AF:

0.000167

AC:

AN:

54020

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000297

AC:

250

AN:

841855

Other (OTH)

AF:

0.000456

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000143

AC:

AN:

111711

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

33915

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30750

American (AMR)

AF:

0.000380

AC:

AN:

10513

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3507

South Asian (SAS)

AF:

0.00

AC:

AN:

2661

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

53127

Other (OTH)

AF:

0.00

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.000219

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.097

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.4

PhyloP100

5.5

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.51

Sift

Benign

0.041

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.47

MVP

0.75

MPC

0.0017

ClinPred

0.21

GERP RS

2.5

Varity_R

0.54

gMVP

0.70

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over