Genetic Variant NXPH3:p.Asn241Ser (chr17-49579263-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007225.4(NXPH3):c.722A>G(p.Asn241Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000484 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NXPH3
NM_007225.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

Variant links:

Genes affected

NXPH3 (HGNC:8077): (neurexophilin 3) Predicted to enable signaling receptor binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

NXPH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3099764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPH3	NM_007225.4 link	c.722A>G	p.Asn241Ser	missense_variant	Exon 2 of 2	ENST00000328741.6	NP_009156.2	O95157

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NXPH3	ENST00000328741.6 link	c.722A>G	p.Asn241Ser	missense_variant	Exon 2 of 2	1	NM_007225.4	ENSP00000329295.6	O95157
NXPH3	ENST00000513748.1 link	c.705+17A>G		intron_variant	Intron 2 of 2	1		ENSP00000421168.1	D6RGW2
NXPH3	ENST00000570453.1 link	n.630A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

239438

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130332

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1447764

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.722A>G (p.N241S) alteration is located in exon 2 (coding exon 2) of the NXPH3 gene. This alteration results from a A to G substitution at nucleotide position 722, causing the asparagine (N) at amino acid position 241 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

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Benign

0.026

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.015

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.28

Sift

Benign

0.045

Sift4G

Pathogenic

0.0

Polyphen

0.0060

Vest4

0.23

MutPred

0.79

Gain of disorder (P = 0.0577);

MVP

0.16

MPC

0.31

ClinPred

0.58

GERP RS

4.3

Varity_R

0.40

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

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

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