Variant 4-75921029-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014435.4(NAAA):c.761C>T(p.Ser254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,608,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S254C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

NAAA
NM_014435.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.177

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06612477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAAA	NM_014435.4 linkuse as main transcript	c.761C>T	p.Ser254Phe	missense_variant	6/11	ENST00000286733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAAA	ENST00000286733.9 linkuse as main transcript	c.761C>T	p.Ser254Phe	missense_variant	6/11	5	NM_014435.4	P1	Q02083-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000288

AC:

AN:

243070

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

132018

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000310

Gnomad ASJ exome

AF:

0.00233

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000103

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000340

Gnomad OTH exome

AF:

0.000507

GnomAD4 exome

AF:

0.000250

AC:

364

AN:

1456204

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

196

AN XY:

724356

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00254

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000824

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.000515

GnomAD4 genome

AF:

0.000256

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000418

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.000724

AC:

ExAC

AF:

0.000281

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

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

Jun 11, 2021

The c.761C>T (p.S254F) alteration is located in exon 6 (coding exon 6) of the NAAA gene. This alteration results from a C to T substitution at nucleotide position 761, causing the serine (S) at amino acid position 254 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

0.087

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;.;D

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.95

P;.;P

Vest4

0.29

MVP

0.70

MPC

0.33

ClinPred

0.072

GERP RS

-0.21

Varity_R

0.17

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over