12-56712876-A-T

Variant names:

• chr12-56712876-A-T
• rs4788
• NM_001365896.1:c.6132T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001365896.1(NACA):​c.6132T>A​(p.Ile2044Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 1,613,982 control chromosomes in the GnomAD database, including 446,941 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.78 (46302 hom., cov: 32)
  • Exomes 𝑓: 0.74 (400639 hom.)
• Consequence: NACA NM_001365896.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 35 publications found

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]

ENSG00000306812 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365896.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NACA	NM_001365896.1	MANE Select	c.6132T>A	p.Ile2044Ile	synonymous	Exon 8 of 9	NP_001352825.1	E9PAV3-1
	NACA	NM_001113203.3		c.2673T>A	p.Ile891Ile	synonymous	Exon 10 of 11	NP_001106674.2	E9PAV3-2
	NACA	NM_001320194.2		c.543T>A	p.Ile181Ile	synonymous	Exon 7 of 7	NP_001307123.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NACA	ENST00000454682.6	TSL:5 MANE Select	c.6132T>A	p.Ile2044Ile	synonymous	Exon 8 of 9	ENSP00000403817.1	E9PAV3-1
	NACA	ENST00000356769.7	TSL:1	c.543T>A	p.Ile181Ile	synonymous	Exon 7 of 8	ENSP00000349212.3	Q13765-1
	NACA	ENST00000393891.8	TSL:1	c.543T>A	p.Ile181Ile	synonymous	Exon 7 of 8	ENSP00000377469.4	Q13765-1

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118173 AN: 152006 Hom.: 46248 Cov.: 32

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.790

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.767

GnomAD2 exomes AF: 0.771 AC: 193946 AN: 251428 AF XY: 0.770

Gnomad AFR exome AF: 0.855

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.739 AC: 1080281 AN: 1461858 Hom.: 400639 Cov.: 69 AF XY: 0.741 AC XY: 539103 AN XY: 727230

African (AFR) AF: 0.859 AC: 28755 AN: 33480

American (AMR) AF: 0.805 AC: 36007 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 18330 AN: 26134

East Asian (EAS) AF: 0.695 AC: 27580 AN: 39696

South Asian (SAS) AF: 0.829 AC: 71507 AN: 86258

European-Finnish (FIN) AF: 0.819 AC: 43764 AN: 53410

Middle Eastern (MID) AF: 0.718 AC: 4140 AN: 5768

European-Non Finnish (NFE) AF: 0.724 AC: 805582 AN: 1111994

Other (OTH) AF: 0.739 AC: 44616 AN: 60394

GnomAD4 genome AF: 0.778 AC: 118284 AN: 152124 Hom.: 46302 Cov.: 32 AF XY: 0.783 AC XY: 58254 AN XY: 74368

African (AFR) AF: 0.849 AC: 35242 AN: 41494

American (AMR) AF: 0.790 AC: 12054 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2411 AN: 3468

East Asian (EAS) AF: 0.740 AC: 3835 AN: 5182

South Asian (SAS) AF: 0.826 AC: 3985 AN: 4822

European-Finnish (FIN) AF: 0.830 AC: 8790 AN: 10588

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.727 AC: 49408 AN: 67992

Other (OTH) AF: 0.770 AC: 1629 AN: 2116

Alfa AF: 0.740 Hom.: 13624

Bravo AF: 0.774

Asia WGS AF: 0.804 AC: 2795 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.719

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.6
DANN	Benign	0.73
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=77/23	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4788; hg19: chr12-57106660; COSMIC: COSV108175877; COSMIC: COSV108175877;