rs324420

Positions:

• chr1-46405089-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001441.3(FAAH):​c.385C>A​(p.Pro129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,776 control chromosomes in the GnomAD database, including 41,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5577 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35488 hom.)
• Consequence: FAAH NM_001441.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.386

Genes affected

FAAH (HGNC:3553): (fatty acid amide hydrolase) This gene encodes a protein that is responsible for the hydrolysis of a number of primary and secondary fatty acid amides, including the neuromodulatory compounds anandamide and oleamide. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037901402).
• BP6: Variant 1-46405089-C-A is Benign according to our data. Variant chr1-46405089-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 6724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAAH	NM_001441.3	c.385C>A	p.Pro129Thr	missense_variant	3/15	ENST00000243167.9	NP_001432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAAH	ENST00000243167.9	c.385C>A	p.Pro129Thr	missense_variant	3/15	1	NM_001441.3	ENSP00000243167	P1
FAAH	ENST00000468718.5	n.405C>A		non_coding_transcript_exon_variant	3/5	3
FAAH	ENST00000493735.5	n.363C>A		non_coding_transcript_exon_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39514 AN: 152014 Hom.: 5570 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.236 AC: 59345 AN: 251362 Hom.: 7639 AF XY: 0.225 AC XY: 30632 AN XY: 135898

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.215 AC: 314560 AN: 1461644 Hom.: 35488 Cov.: 40 AF XY: 0.214 AC XY: 155434 AN XY: 727132

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.260 AC: 39553 AN: 152132 Hom.: 5577 Cov.: 33 AF XY: 0.261 AC XY: 19409 AN XY: 74364

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.239

Alfa AF: 0.207 Hom.: 8871

Bravo AF: 0.267

TwinsUK AF: 0.206 AC: 765

ALSPAC AF: 0.190 AC: 731

ESP6500AA AF: 0.348 AC: 1533

ESP6500EA AF: 0.200 AC: 1722

ExAC AF: 0.233 AC: 28288

Asia WGS AF: 0.192 AC: 669 AN: 3478

EpiCase AF: 0.193

EpiControl AF: 0.189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FAAH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Polysubstance abuse, susceptibility to Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

FAAH POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.59
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.061
Sift	Benign	0.32	T
Sift4G	Benign	0.46	T
Polyphen		0.014	B
Vest4		0.035
MPC		1.2
ClinPred		0.0028	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.56

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: rs324420; hg19: chr1-46870761; COSMIC: COSV54544102; COSMIC: COSV54544102;