16-15038576-C-T

Variant names:

• chr16-15038576-C-T
• rs751742881
• NM_173474.4:c.751G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173474.4(NTAN1):​c.751G>A​(p.Glu251Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NTAN1 NM_173474.4 missense, splice_region
• Scores: Splicing: ADA: 0.9236
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.215092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173474.4. 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
	NTAN1	NM_173474.4	MANE Select	c.751G>A	p.Glu251Lys	missense splice_region	Exon 9 of 10	NP_775745.1	Q96AB6
	NTAN1	NM_001270766.2		c.436G>A	p.Glu146Lys	missense splice_region	Exon 8 of 9	NP_001257695.1	A0A087X0T5
	NTAN1	NM_001270767.2		c.436G>A	p.Glu146Lys	missense splice_region	Exon 7 of 8	NP_001257696.1	A0A087X0T5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTAN1	ENST00000287706.8	TSL:1 MANE Select	c.751G>A	p.Glu251Lys	missense splice_region	Exon 9 of 10	ENSP00000287706.3	Q96AB6
	PDXDC1	ENST00000535621.6	TSL:1	c.1399+8520C>T		intron	N/A	ENSP00000437835.2	Q86XE2
	NTAN1	ENST00000622833.4	TSL:2	c.436G>A	p.Glu146Lys	missense splice_region	Exon 7 of 8	ENSP00000483643.1	A0A087X0T5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249630 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 7.32e-7 AC: 1 AN: 1366000 Hom.: 0 Cov.: 21 AF XY: 0.00000146 AC XY: 1 AN XY: 684934

African (AFR) AF: 0.00 AC: 0 AN: 31460

American (AMR) AF: 0.00 AC: 0 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025548

Other (OTH) AF: 0.00 AC: 0 AN: 57120

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.0095
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.75	N
PhyloP100		2.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.068
Sift	Benign	0.26	T
Sift4G	Benign	0.38	T
Polyphen		0.10	B
Vest4		0.34
MutPred		0.34		Gain of methylation at E251 (P = 0.0084)
MVP		0.43
MPC		0.19
ClinPred		0.43	T
GERP RS		6.2
Varity_R		0.21
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.68
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: rs751742881; hg19: chr16-15132433;