12-57225416-C-A

Position:

• chr12-57225416-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007224.4(NXPH4):​c.596C>A​(p.Ala199Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: NXPH4 NM_007224.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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]

ACMG classification

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=0.092208475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPH4	NM_007224.4	c.596C>A	p.Ala199Glu	missense_variant	2/2	ENST00000349394.6	NP_009155.1
NXPH4	XM_017018747.2	c.400+196C>A		intron_variant			XP_016874236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPH4	ENST00000349394.6	c.596C>A	p.Ala199Glu	missense_variant	2/2	1	NM_007224.4	ENSP00000333593	P1
NXPH4	ENST00000555154.1	n.647C>A		non_coding_transcript_exon_variant	2/2	3
NXPH4	ENST00000556415.1	c.*723C>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000452288

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.596C>A (p.A199E) alteration is located in exon 2 (coding exon 2) of the NXPH4 gene. This alteration results from a C to A substitution at nucleotide position 596, causing the alanine (A) at amino acid position 199 to be replaced by a glutamic acid (E). 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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.043
Sift	Benign	0.23	T
Sift4G	Benign	0.10	T
Polyphen		0.25	B
Vest4		0.30
MutPred		0.43		Gain of catalytic residue at G203 (P = 0.001);
MVP		0.15
MPC		1.3
ClinPred		0.084	T
GERP RS		0.011
Varity_R		0.12
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57619199;