chr12-56716216-G-A

Position:

• chr12-56716216-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365896.1(NACA):​c.5314C>T​(p.Pro1772Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,613,764 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (12 hom.)
• Consequence: NACA NM_001365896.1 missense
• Scores: Splicing: ADA: 0.002389
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.977

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00409168).
• BP6: Variant 12-56716216-G-A is Benign according to our data. Variant chr12-56716216-G-A is described in ClinVar as [Benign]. Clinvar id is 713130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACA	NM_001365896.1	c.5314C>T	p.Pro1772Ser	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.5314C>T	p.Pro1772Ser	missense_variant	3/9	5	NM_001365896.1	ENSP00000403817.1
ENSG00000285625	ENST00000647707.1	c.512-1529C>T		intron_variant				ENSP00000497880.1
NACA	ENST00000547914.5	n.71-1529C>T		intron_variant		5		ENSP00000446745.1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152180 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00277 AC: 688 AN: 248522 Hom.: 3 AF XY: 0.00286 AC XY: 386 AN XY: 135148

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00378 AC: 5521 AN: 1461466 Hom.: 12 Cov.: 46 AF XY: 0.00370 AC XY: 2692 AN XY: 727000

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152298 Hom.: 2 Cov.: 31 AF XY: 0.00278 AC XY: 207 AN XY: 74486

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00479 Hom.: 1

Bravo AF: 0.00301

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000638 AC: 2

ESP6500EA AF: 0.00530 AC: 38

ExAC AF: 0.00255 AC: 307

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.052	T
Polyphen		0.45	B
Vest4		0.15
MVP		0.52
ClinPred		0.061	T
GERP RS		3.8
Varity_R		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.024
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: rs183828032; hg19: chr12-57110000;