Genetic Variant NXPE1:p.Asp354Asn (chr11-114522927-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001395504.1(NXPE1):c.1060G>A(p.Asp354Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,274 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 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NXPE1
NM_001395504.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

Variant links:

Genes affected

NXPE1 (HGNC:28527): (neurexophilin and PC-esterase domain family member 1) Predicted to be located in extracellular region. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NXPE1 links:

NXPE2 (HGNC:26331): (neurexophilin and PC-esterase domain family member 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NXPE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPE1	NM_001395504.1 link	c.1060G>A	p.Asp354Asn	missense_variant	Exon 8 of 9	ENST00000534921.3	NP_001382433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NXPE1	ENST00000534921.3 link	c.1060G>A	p.Asp354Asn	missense_variant	Exon 8 of 9	3	NM_001395504.1	ENSP00000439503.2	Q8N323-1
NXPE1	ENST00000251921.6 link	c.634G>A	p.Asp212Asn	missense_variant	Exon 5 of 6	1		ENSP00000251921.2	Q8N323-2
NXPE1	ENST00000536271.5 link	n.1452G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1
NXPE1	ENST00000696071.1 link	c.1060G>A	p.Asp354Asn	missense_variant	Exon 7 of 8			ENSP00000512373.1	Q8N323-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000119

AC:

AN:

251118

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00000753

AC:

AN:

1461290

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

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:

0.0000461

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.000169

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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.634G>A (p.D212N) alteration is located in exon 5 (coding exon 3) of the NXPE1 gene. This alteration results from a G to A substitution at nucleotide position 634, causing the aspartic acid (D) at amino acid position 212 to be replaced by an asparagine (N). 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

0.66

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.86

.;D;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.2

M;.;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.9

.;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

D;.;D

Vest4

0.81, 0.82

MVP

0.62

MPC

0.15

ClinPred

0.99

GERP RS

4.5

Varity_R

0.75

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over