12-57225118-G-A

Position:

• chr12-57225118-G-A

Variant summary

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

The NM_007224.4(NXPH4):​c.298G>A​(p.Ala100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,373,726 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: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NXPH4 NM_007224.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

NXPH4 (HGNC:8078): (neurexophilin 4) Predicted to enable signaling receptor binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

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=0.21812862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPH4	NM_007224.4	c.298G>A	p.Ala100Thr	missense_variant	2/2	ENST00000349394.6	NP_009155.1
NXPH4	XM_017018747.2	c.298G>A	p.Ala100Thr	missense_variant	2/3		XP_016874236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPH4	ENST00000349394.6	c.298G>A	p.Ala100Thr	missense_variant	2/2	1	NM_007224.4	ENSP00000333593	P1
NXPH4	ENST00000555154.1	n.349G>A		non_coding_transcript_exon_variant	2/2	3
NXPH4	ENST00000556415.1	c.*425G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000452288

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1373726 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 675220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 27, 2023

The c.298G>A (p.A100T) alteration is located in exon 2 (coding exon 2) of the NXPH4 gene. This alteration results from a G to A substitution at nucleotide position 298, causing the alanine (A) at amino acid position 100 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.93	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.21
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.055
MPC		1.1
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.096
gMVP		0.34

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: chr12-57618901;