12-56713102-G-A

Position:

• chr12-56713102-G-A

Variant summary

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

The NM_001365896.1(NACA):​c.6059C>T​(p.Thr2020Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NACA NM_001365896.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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]

NACA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACA	NM_001365896.1	c.6059C>T	p.Thr2020Ile	missense_variant	7/9	ENST00000454682.6	NP_001352825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACA	ENST00000454682.6	c.6059C>T	p.Thr2020Ile	missense_variant	7/9	5	NM_001365896.1	ENSP00000403817.1
NACA	ENST00000547914.5	n.*106C>T		non_coding_transcript_exon_variant	5/7	5		ENSP00000446745.1
NACA	ENST00000547914.5	n.*106C>T		3_prime_UTR_variant	5/7	5		ENSP00000446745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000151

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

Jun 18, 2024

The c.2600C>T (p.T867I) alteration is located in exon 9 (coding exon 8) of the NACA gene. This alteration results from a C to T substitution at nucleotide position 2600, causing the threonine (T) at amino acid position 867 to be replaced by an isoleucine (I). 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	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T;.;T;T;T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T;T;.;.;.;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	.;.;.;L;L;L;.;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D;N;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.12	T;D;D;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;D;T;T;T;T;T;T
Polyphen		0.79, 0.31	.;P;.;B;B;B;.;B;.
Vest4		0.64, 0.60, 0.38, 0.44, 0.45, 0.40
MutPred		0.22		.;Loss of glycosylation at T2020 (P = 0.0118);.;.;.;.;.;.;.;
MVP		0.63
MPC		1.5
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.79

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: rs1953261150; hg19: chr12-57106886;