7-8751356-C-G

Position:

• chr7-8751356-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_152745.3(NXPH1):​c.403C>G​(p.Leu135Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NXPH1 NM_152745.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

Genes affected

NXPH1 (HGNC:20693): (neurexophilin 1) This gene is a member of the neurexophilin family and encodes a secreted protein with a variable N-terminal domain, a highly conserved, N-glycosylated central domain, a short linker region, and a cysteine-rich C-terminal domain. This protein forms a very tight complex with alpha neurexins, a group of proteins that promote adhesion between dendrites and axons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPH1	NM_152745.3	c.403C>G	p.Leu135Val	missense_variant	3/3	ENST00000405863.6	NP_689958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPH1	ENST00000405863.6	c.403C>G	p.Leu135Val	missense_variant	3/3	1	NM_152745.3	ENSP00000384551.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461576 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727064

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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

Aug 21, 2024

The c.403C>G (p.L135V) alteration is located in exon 3 (coding exon 2) of the NXPH1 gene. This alteration results from a C to G substitution at nucleotide position 403, causing the leucine (L) at amino acid position 135 to be replaced by a valine (V). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;T;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.50
MutPred		0.86		Gain of methylation at K132 (P = 0.0954);Gain of methylation at K132 (P = 0.0954);Gain of methylation at K132 (P = 0.0954);.;
MVP		0.12
MPC		0.90
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.39

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

Other links and lift over

dbSNP: rs762855683; hg19: chr7-8790986;