Genetic Variant NM_007224.4:c.499T>C (chr12-57225319-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_007224.4(NXPH4):c.499T>C(p.Trp167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,076 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: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NXPH4
NM_007224.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.884

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:

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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=0.12959072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPH4	NM_007224.4 link	c.499T>C	p.Trp167Arg	missense_variant	Exon 2 of 2	ENST00000349394.6	NP_009155.1	O95158
NXPH4	XM_017018747.2 link	c.400+99T>C		intron_variant	Intron 2 of 2		XP_016874236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NXPH4	ENST00000349394.6 link	c.499T>C	p.Trp167Arg	missense_variant	Exon 2 of 2	1	NM_007224.4	ENSP00000333593.6	O95158
NXPH4	ENST00000555154.1 link	n.550T>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
NXPH4	ENST00000556415.1 link	n.*626T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000452288.1	G3V5C5
NXPH4	ENST00000556415.1 link	n.*626T>C		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000452288.1	G3V5C5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000968

AC:

AN:

206516

Hom.:

AF XY:

0.00000903

AC XY:

AN XY:

110704

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:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1406076

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694028

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:

0.00000276

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499T>C (p.W167R) alteration is located in exon 2 (coding exon 2) of the NXPH4 gene. This alteration results from a T to C substitution at nucleotide position 499, causing the tryptophan (W) at amino acid position 167 to be replaced by an arginine (R). 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

Uncertain

0.50

BayesDel_addAF

Benign

0.0030

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.018

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.48

M_CAP

Benign

0.033

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.15

Vest4

0.25

MutPred

0.60

Gain of disorder (P = 3e-04);

MVP

0.21

MPC

1.5

ClinPred

0.21

GERP RS

3.1

Varity_R

0.29

gMVP

0.67

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