11-114580291-T-C

Position:

• chr11-114580291-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001077639.2(NXPE4):​c.940A>G​(p.Thr314Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: NXPE4 NM_001077639.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.497

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066583395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPE4	NM_001077639.2	c.940A>G	p.Thr314Ala	missense_variant	5/6	ENST00000375478.4	NP_001071107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPE4	ENST00000375478.4	c.940A>G	p.Thr314Ala	missense_variant	5/6	1	NM_001077639.2	ENSP00000364627.3
NXPE4	ENST00000424261.6	c.88A>G	p.Thr30Ala	missense_variant	5/6	1		ENSP00000401503.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

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

Sep 20, 2023

The c.940A>G (p.T314A) alteration is located in exon 5 (coding exon 4) of the NXPE4 gene. This alteration results from a A to G substitution at nucleotide position 940, causing the threonine (T) at amino acid position 314 to be replaced by an alanine (A). 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	0.062
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.0027	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.013
Sift	Benign	0.076	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.0040	.;B
Vest4		0.10
MutPred		0.35		.;Gain of MoRF binding (P = 0.0974);
MVP		0.014
MPC		0.058
ClinPred		0.066	T
GERP RS		-9.5
Varity_R		0.037
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-114451013;