12-57225466-C-G

Variant names:

• chr12-57225466-C-G
• rs756087156
• NM_007224.4:c.646C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007224.4(NXPH4):​c.646C>G​(p.Leu216Val) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L216I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NXPH4 NM_007224.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.782
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085295975).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007224.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXPH4	NM_007224.4	MANE Select	c.646C>G	p.Leu216Val	missense	Exon 2 of 2	NP_009155.1	O95158

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXPH4	ENST00000349394.6	TSL:1 MANE Select	c.646C>G	p.Leu216Val	missense	Exon 2 of 2	ENSP00000333593.6	O95158
	NXPH4	ENST00000556415.1	TSL:2	n.*773C>G		non_coding_transcript_exon	Exon 3 of 3	ENSP00000452288.1	G3V5C5
	NXPH4	ENST00000556415.1	TSL:2	n.*773C>G		3_prime_UTR	Exon 3 of 3	ENSP00000452288.1	G3V5C5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.84
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.78
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.019
Sift	Benign	0.055	T
Sift4G	Uncertain	0.020	D
Polyphen		0.29	B
Vest4		0.16
MutPred		0.42		Gain of catalytic residue at G214 (P = 0)
MVP		0.076
MPC		0.86
ClinPred		0.082	T
GERP RS		3.0
Varity_R		0.074
gMVP		0.40
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs756087156; hg19: chr12-57619249;