chr11-114571299-C-T

Position:

• chr11-114571299-C-T

Variant summary

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

The NM_001077639.2(NXPE4):​c.1274G>A​(p.Gly425Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NXPE4 NM_001077639.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

Genes affected

NXPE4 (HGNC:23117): (neurexophilin and PC-esterase domain family member 4) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

NXPE2 (HGNC:26331): (neurexophilin and PC-esterase domain family member 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPE4	NM_001077639.2	c.1274G>A	p.Gly425Glu	missense_variant	6/6	ENST00000375478.4	NP_001071107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPE4	ENST00000375478.4	c.1274G>A	p.Gly425Glu	missense_variant	6/6	1	NM_001077639.2	ENSP00000364627.3
NXPE4	ENST00000424261.6	c.422G>A	p.Gly141Glu	missense_variant	6/6	1		ENSP00000401503.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461736 Hom.: 0 Cov.: 49 AF XY: 0.00000963 AC XY: 7 AN XY: 727172

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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 29, 2023

The c.1274G>A (p.G425E) alteration is located in exon 6 (coding exon 5) of the NXPE4 gene. This alteration results from a G to A substitution at nucleotide position 1274, causing the glycine (G) at amino acid position 425 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	0.24
BayesDel_addAF	Benign	0.0092	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.8	.;H
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.93	.;P
Vest4		0.39
MutPred		0.66		.;Gain of solvent accessibility (P = 0.0171);
MVP		0.40
MPC		0.38
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.62

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: rs1948878550; hg19: chr11-114442021; COSMIC: COSV64944488;