1-46394428-T-C

Position:

• chr1-46394428-T-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.80T>C​(p.Val27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,312,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FAAH NM_001441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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=0.23535568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAAH	NM_001441.3	c.80T>C	p.Val27Ala	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.80T>C	p.Val27Ala	missense_variant	1/15	1	NM_001441.3	ENSP00000243167	P1
FAAH	ENST00000468718.5	n.100T>C		non_coding_transcript_exon_variant	1/5	3
FAAH	ENST00000493735.5	n.58T>C		non_coding_transcript_exon_variant	1/8	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.62e-7 AC: 1 AN: 1312326 Hom.: 0 Cov.: 30 AF XY: 0.00000155 AC XY: 1 AN XY: 646466

Gnomad4 AFR exome AF: 0.00

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: 9.58e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Oct 20, 2023

The c.80T>C (p.V27A) alteration is located in exon 1 (coding exon 1) of the FAAH gene. This alteration results from a T to C substitution at nucleotide position 80, causing the valine (V) at amino acid position 27 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	Benign	0.082
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.92	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.050	D
Sift4G	Uncertain	0.023	D
Polyphen		0.071	B
Vest4		0.26
MutPred		0.38		Gain of disorder (P = 0.0514);
MVP		0.76
MPC		0.40
ClinPred		0.15	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.33

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: rs936672412; hg19: chr1-46860100;