chr1-46394494-G-C

Position:

• chr1-46394494-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001441.3(FAAH):​c.146G>C​(p.Arg49Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R49Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAAH NM_001441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.540

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070586294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAAH	NM_001441.3	c.146G>C	p.Arg49Pro	missense_variant	1/15	ENST00000243167.9	NP_001432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAAH	ENST00000243167.9	c.146G>C	p.Arg49Pro	missense_variant	1/15	1	NM_001441.3	ENSP00000243167.8
FAAH	ENST00000468718.5	n.166G>C		non_coding_transcript_exon_variant	1/5	3
FAAH	ENST00000493735.5	n.124G>C		non_coding_transcript_exon_variant	1/8	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Aug 10, 2024

The c.146G>C (p.R49P) alteration is located in exon 1 (coding exon 1) of the FAAH gene. This alteration results from a G to C substitution at nucleotide position 146, causing the arginine (R) at amino acid position 49 to be replaced by a proline (P). 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	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.041
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.091	B
Vest4		0.25
MutPred		0.38		Loss of methylation at R49 (P = 0.0145);
MVP		0.23
MPC		0.62
ClinPred		0.084	T
GERP RS		1.2
Varity_R		0.33
gMVP		0.64

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: rs1417337990; hg19: chr1-46860166;