12-56716126-G-A

Position:

• chr12-56716126-G-A

Variant summary

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

The NM_001365896.1(NACA):​c.5404C>T​(p.Leu1802Phe) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NACA NM_001365896.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.341

Genes affected

NACA (HGNC:7629): (nascent polypeptide associated complex subunit alpha) This gene encodes a protein that associates with basic transcription factor 3 (BTF3) to form the nascent polypeptide-associated complex (NAC). This complex binds to nascent proteins that lack a signal peptide motif as they emerge from the ribosome, blocking interaction with the signal recognition particle (SRP) and preventing mistranslocation to the endoplasmic reticulum. This protein is an IgE autoantigen in atopic dermatitis patients. Alternative splicing results in multiple transcript variants, but the full length nature of some of these variants, including those encoding very large proteins, has not been determined. There are multiple pseudogenes of this gene on different chromosomes. [provided by RefSeq, Feb 2016]

ENSG00000285625 (HGNC:):

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=0.08773729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACA	NM_001365896.1	c.5404C>T	p.Leu1802Phe	missense_variant	3/9	ENST00000454682.6	NP_001352825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACA	ENST00000454682.6	c.5404C>T	p.Leu1802Phe	missense_variant	3/9	5	NM_001365896.1	ENSP00000403817.1
ENSG00000285625	ENST00000647707.1	c.512-1439C>T		intron_variant				ENSP00000497880.1
NACA	ENST00000547914.5	n.71-1439C>T		intron_variant		5		ENSP00000446745.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 31

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

May 23, 2023

The c.1945C>T (p.L649F) alteration is located in exon 5 (coding exon 4) of the NACA gene. This alteration results from a C to T substitution at nucleotide position 1945, causing the leucine (L) at amino acid position 649 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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.41	T;T
Polyphen		0.12	B;.
Vest4		0.065
MutPred		0.25		Gain of catalytic residue at V1798 (P = 2e-04);.;
MVP		0.29
MPC		0.11
ClinPred		0.50	T
GERP RS		1.9
Varity_R		0.20
gMVP		0.065

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr12-57109910;