16-15038117-G-T

Position:

• chr16-15038117-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173474.4(NTAN1):​c.847C>A​(p.His283Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,606,596 control chromosomes in the GnomAD database, including 82,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7522 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74754 hom.)
• Consequence: NTAN1 NM_173474.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.417

Genes affected

NTAN1 (HGNC:29909): (N-terminal asparagine amidase) The protein encoded by this gene functions in a step-wise process of protein degradation through the N-end rule pathway. This protein acts as a tertiary destabilizing enzyme that deamidates N-terminal L-Asn residues on proteins to produce N-terminal L-Asp. L-Asp substrates are subsequently conjugated to L-Arg, which is recognized by specific E3 ubiquitin ligases and targeted to the proteasome. Pseudogenes of this gene are located on the long arms of chromosomes 8, 10 and 12. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

PDXDC1 (HGNC:28995): (pyridoxal dependent decarboxylase domain containing 1) Enables cadherin binding activity. Predicted to be involved in carboxylic acid metabolic process. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.744131E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTAN1	NM_173474.4	c.847C>A	p.His283Asn	missense_variant	10/10	ENST00000287706.8	NP_775745.1
PDXDC1	NM_015027.4	c.*1842G>T		3_prime_UTR_variant	23/23	ENST00000396410.9	NP_055842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTAN1	ENST00000287706.8	c.847C>A	p.His283Asn	missense_variant	10/10	1	NM_173474.4	ENSP00000287706	P1
PDXDC1	ENST00000396410.9	c.*1842G>T		3_prime_UTR_variant	23/23	1	NM_015027.4	ENSP00000379691	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46250 AN: 151882 Hom.: 7500 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.350 AC: 86778 AN: 247938 Hom.: 16687 AF XY: 0.345 AC XY: 46292 AN XY: 134286

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.402

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.314 AC: 456390 AN: 1454596 Hom.: 74754 Cov.: 30 AF XY: 0.315 AC XY: 228142 AN XY: 723850

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.380

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.305 AC: 46320 AN: 152000 Hom.: 7522 Cov.: 32 AF XY: 0.311 AC XY: 23079 AN XY: 74294

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.323

Alfa AF: 0.305 Hom.: 17328

Bravo AF: 0.312

TwinsUK AF: 0.289 AC: 1070

ALSPAC AF: 0.275 AC: 1058

ESP6500AA AF: 0.226 AC: 992

ESP6500EA AF: 0.300 AC: 2583

ExAC AF: 0.341 AC: 41381

Asia WGS AF: 0.426 AC: 1480 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.68
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.050	T;.;T
MetaRNN	Benign	0.000067	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.2	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.37	N;.;.
REVEL	Benign	0.056
Sift	Benign	0.50	T;.;.
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.028
MPC		0.16
ClinPred		0.0011	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1136001; hg19: chr16-15131974; COSMIC: COSV55074343; COSMIC: COSV55074343;