Variant chr4-75940011-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014435.4(NAAA):c.361G>A(p.Glu121Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NAAA
NM_014435.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

Variant links:

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]

NAAA links:

NAAA (HGNC:):

NAAA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAAA	NM_014435.4 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	2/11	ENST00000286733.9	NP_055250.2	Q02083-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAAA	ENST00000286733.9 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	2/11	5	NM_014435.4	ENSP00000286733.4		Q02083-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727078

show subpopulations

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.361G>A (p.E121K) alteration is located in exon 2 (coding exon 2) of the NAAA gene. This alteration results from a G to A substitution at nucleotide position 361, causing the glutamic acid (E) at amino acid position 121 to be replaced by a lysine (K). 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

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.7

M;M;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.94

MutPred

0.80

Gain of ubiquitination at E121 (P = 0.03);Gain of ubiquitination at E121 (P = 0.03);.;Gain of ubiquitination at E121 (P = 0.03);

MVP

0.87

MPC

0.63

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over