4-75936121-T-A

Variant summary

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

The NM_014435.4(NAAA):c.486A>T(p.Leu162Phe) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NAAA NM_014435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.155

Genes affected

NAAA (HGNC:736): (N-acylethanolamine acid amidase) Enables N-(long-chain-acyl)ethanolamine deacylase activity; N-acylsphingosine amidohydrolase activity; and fatty acid amide hydrolase activity. Involved in several processes, including N-acylethanolamine metabolic process; N-acylphosphatidylethanolamine metabolic process; and sphingosine metabolic process. Located in lysosome. Is extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.18575463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAAA	NM_014435.4	c.486A>T	p.Leu162Phe	missense_variant	3/11	ENST00000286733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAAA	ENST00000286733.9	c.486A>T	p.Leu162Phe	missense_variant	3/11	5	NM_014435.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 19, 2022

The c.486A>T (p.L162F) alteration is located in exon 3 (coding exon 3) of the NAAA gene. This alteration results from a A to T substitution at nucleotide position 486, causing the leucine (L) at amino acid position 162 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	0.93	N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.91	P;.;P;B
Vest4		0.14
MutPred		0.33		Gain of methylation at K163 (P = 0.0368);Gain of methylation at K163 (P = 0.0368);.;Gain of methylation at K163 (P = 0.0368);
MVP		0.67
MPC		0.72
ClinPred		0.69	D
GERP RS		3.5
Varity_R		0.26
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-76857274;