12-56715898-T-C

Position:

• chr12-56715898-T-C

Variant summary

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

The NM_001365896.1(NACA):​c.5632A>G​(p.Lys1878Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NACA NM_001365896.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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=0.14896557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACA	NM_001365896.1	c.5632A>G	p.Lys1878Glu	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.5632A>G	p.Lys1878Glu	missense_variant	3/9	5	NM_001365896.1	ENSP00000403817.1
ENSG00000285625	ENST00000647707.1	c.512-1211A>G		intron_variant				ENSP00000497880.1
NACA	ENST00000547914.5	n.71-1211A>G		intron_variant		5		ENSP00000446745.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364250 Hom.: 0 Cov.: 29 AF XY: 0.00000150 AC XY: 1 AN XY: 667842

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: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Oct 12, 2021

The c.2173A>G (p.K725E) alteration is located in exon 5 (coding exon 4) of the NACA gene. This alteration results from a A to G substitution at nucleotide position 2173, causing the lysine (K) at amino acid position 725 to be replaced by a glutamic acid (E). 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	0.27
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.071
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	1.0	T;T
Polyphen		0.29	B;.
Vest4		0.37
MutPred		0.33		Loss of methylation at K1878 (P = 0.0049);.;
MVP		0.33
MPC		0.055
ClinPred		0.68	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr12-57109682;