4-75921069-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014435.4(NAAA):c.721C>T(p.Pro241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,446,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NAAA NM_014435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAAA	NM_014435.4	c.721C>T	p.Pro241Ser	missense_variant	6/11	ENST00000286733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAAA	ENST00000286733.9	c.721C>T	p.Pro241Ser	missense_variant	6/11	5	NM_014435.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1446634 Hom.: 0 Cov.: 32 AF XY: 0.00000556 AC XY: 4 AN XY: 719176

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: 0.00000903

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

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

Aug 24, 2023

The c.721C>T (p.P241S) 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 721, causing the proline (P) at amino acid position 241 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.52
Sift	Benign	0.076	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.77	P;.;B
Vest4		0.92
MutPred		0.43		Loss of methylation at K239 (P = 0.0923);Loss of methylation at K239 (P = 0.0923);.;
MVP		0.84
MPC		0.82
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.80

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: rs1247213456; hg19: chr4-76842222;