Variant chr12-57225451-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007224.4(NXPH4):c.631G>T(p.Ala211Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,602,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

NXPH4
NM_007224.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

Genes affected

NXPH4 (HGNC:8078): (neurexophilin 4) Predicted to enable signaling receptor binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

NXPH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.23720056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NXPH4	NM_007224.4 linkuse as main transcript	c.631G>T	p.Ala211Ser	missense_variant	2/2	ENST00000349394.6
NXPH4	XM_017018747.2 linkuse as main transcript	c.401-224G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NXPH4	ENST00000349394.6 linkuse as main transcript	c.631G>T	p.Ala211Ser	missense_variant	2/2	1	NM_007224.4	P1
NXPH4	ENST00000556415.1 linkuse as main transcript	c.*758G>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	2
NXPH4	ENST00000555154.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000856

AC:

AN:

221864

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

123526

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:

0.000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000158

AC:

229

AN:

1450092

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

113

AN XY:

721364

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.000200

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000119

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.631G>T (p.A211S) alteration is located in exon 2 (coding exon 2) of the NXPH4 gene. This alteration results from a G to T substitution at nucleotide position 631, causing the alanine (A) at amino acid position 211 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

0.081

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0046

Eigen

Benign

0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.54

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.53

REVEL

Benign

0.092

Sift

Benign

0.044

Sift4G

Benign

0.069

Polyphen

0.99

Vest4

0.35

MutPred

0.44

Gain of catalytic residue at A211 (P = 0);

MVP

0.088

MPC

1.8

ClinPred

0.21

GERP RS

4.0

Varity_R

0.080

gMVP

0.37

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