16-15038059-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173474.4(NTAN1):c.905G>C(p.Trp302Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,612,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NTAN1 NM_173474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTAN1	NM_173474.4	c.905G>C	p.Trp302Ser	missense_variant	10/10	ENST00000287706.8
PDXDC1	NM_015027.4	c.*1784C>G		3_prime_UTR_variant	23/23	ENST00000396410.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTAN1	ENST00000287706.8	c.905G>C	p.Trp302Ser	missense_variant	10/10	1	NM_173474.4	P1
PDXDC1	ENST00000396410.9	c.*1784C>G		3_prime_UTR_variant	23/23	1	NM_015027.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250092 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135246

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460580 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726648

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74284

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

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

Dec 01, 2022

The c.905G>C (p.W302S) alteration is located in exon 10 (coding exon 10) of the NTAN1 gene. This alteration results from a G to C substitution at nucleotide position 905, causing the tryptophan (W) at amino acid position 302 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;.;T
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-11	D;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.56		Gain of disorder (P = 0.0022);.;.;
MVP		0.98
MPC		0.83
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756432017; hg19: chr16-15131916;