16-15038139-T-A

Variant names:

• chr16-15038139-T-A
• rs553166241
• NM_173474.4:c.825A>T

Variant summary

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

The NM_173474.4(NTAN1):​c.825A>T​(p.Leu275Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,612,378 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: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: NTAN1 NM_173474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07260007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTAN1	NM_173474.4	c.825A>T	p.Leu275Phe	missense_variant	Exon 10 of 10	ENST00000287706.8	NP_775745.1
PDXDC1	NM_015027.4	c.*1864T>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000396410.9	NP_055842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTAN1	ENST00000287706.8	c.825A>T	p.Leu275Phe	missense_variant	Exon 10 of 10	1	NM_173474.4	ENSP00000287706.3
PDXDC1	ENST00000396410.9	c.*1864T>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_015027.4	ENSP00000379691.4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000521 AC: 13 AN: 249326 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134980

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460154 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726488

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74436

Gnomad4 AFR AF: 0.000650

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: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.825A>T (p.L275F) alteration is located in exon 10 (coding exon 10) of the NTAN1 gene. This alteration results from a A to T substitution at nucleotide position 825, causing the leucine (L) at amino acid position 275 to be replaced by a phenylalanine (F). 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	0.18
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	N;.;.
REVEL	Benign	0.089
Sift	Benign	0.069	T;.;.
Sift4G	Benign	0.073	T;T;T
Polyphen		0.033	B;.;.
Vest4		0.34
MutPred		0.29		Gain of methylation at K276 (P = 0.0446);.;.;
MVP		0.39
MPC		0.19
ClinPred		0.050	T
GERP RS		3.6
Varity_R		0.23
gMVP		0.74

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: rs553166241; hg19: chr16-15131996; COSMIC: COSV55075764; COSMIC: COSV55075764;