7-8435727-G-A

Position:

• chr7-8435727-G-A

Variant summary

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

The NM_152745.3(NXPH1):​c.14G>A​(p.Cys5Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NXPH1 NM_152745.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 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=0.17395282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPH1	NM_152745.3	c.14G>A	p.Cys5Tyr	missense_variant	2/3	ENST00000405863.6	NP_689958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPH1	ENST00000405863.6	c.14G>A	p.Cys5Tyr	missense_variant	2/3	1	NM_152745.3	ENSP00000384551.1
NXPH1	ENST00000429542.1	c.14G>A	p.Cys5Tyr	missense_variant	1/2	1		ENSP00000408216.1
NXPH1	ENST00000438764.1	c.14G>A	p.Cys5Tyr	missense_variant	2/3	4		ENSP00000404689.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 09, 2022

The c.14G>A (p.C5Y) alteration is located in exon 2 (coding exon 1) of the NXPH1 gene. This alteration results from a G to A substitution at nucleotide position 14, causing the cysteine (C) at amino acid position 5 to be replaced by a tyrosine (Y). 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	0.059
BayesDel_addAF	Benign	-0.0031	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.031	D;T;D
Polyphen		0.025	B;.;.
Vest4		0.29
MutPred		0.55		Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);
MVP		0.043
MPC		0.42
ClinPred		0.42	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1816182228; hg19: chr7-8475357;