7-8751014-T-A

Variant names:

• chr7-8751014-T-A
• rs776168924
• NM_152745.3:c.61T>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_152745.3(NXPH1):​c.61T>A​(p.Cys21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000014 (0 hom.)
• Consequence: NXPH1 NM_152745.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPH1	NM_152745.3	c.61T>A	p.Cys21Ser	missense_variant	Exon 3 of 3	ENST00000405863.6	NP_689958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NXPH1	ENST00000405863.6	c.61T>A	p.Cys21Ser	missense_variant	Exon 3 of 3	1	NM_152745.3	ENSP00000384551.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 248884 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135018

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461184 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61T>A (p.C21S) alteration is located in exon 3 (coding exon 2) of the NXPH1 gene. This alteration results from a T to A substitution at nucleotide position 61, causing the cysteine (C) at amino acid position 21 to be replaced by a serine (S). 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	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.72
DEOGEN2	Benign	0.20	T;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.12	T;T;T;.
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.17
MutPred		0.93		Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);.;
MVP		0.043
MPC		0.31
ClinPred		0.031	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.32

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: rs776168924; hg19: chr7-8790644;