Genetic Variant NM_007224.4:c.541G>T (chr12-57225361-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007224.4(NXPH4):c.541G>T(p.Ala181Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 in 1,584,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NXPH4
NM_007224.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

Publications

2 publications found

Variant links:

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]

NXPH4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24127805).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007224.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXPH4	NM_007224.4	MANE Select	c.541G>T	p.Ala181Ser	missense	Exon 2 of 2	NP_009155.1	O95158

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NXPH4	ENST00000349394.6	TSL:1 MANE Select	c.541G>T	p.Ala181Ser	missense	Exon 2 of 2	ENSP00000333593.6	O95158
NXPH4	ENST00000555154.1	TSL:3	n.592G>T		non_coding_transcript_exon	Exon 2 of 2
NXPH4	ENST00000556415.1	TSL:2	n.*668G>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000452288.1	G3V5C5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000180

AC:

AN:

222830

AF XY:

0.0000330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000390

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1432282

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

710454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32916

American (AMR)

AF:

0.00

AC:

AN:

42604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24044

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

81604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45596

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00000999

AC:

AN:

1100968

Other (OTH)

AF:

0.0000337

AC:

AN:

59370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000435

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

Eigen

Benign

0.020

Eigen_PC

Benign

0.079

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.69

M_CAP

Benign

0.020

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

3.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.51

REVEL

Benign

0.19

Sift

Benign

0.076

Sift4G

Benign

0.35

Polyphen

0.95

Vest4

0.42

MVP

0.20

MPC

1.6

ClinPred

0.36

GERP RS

4.0

Varity_R

0.12

gMVP

0.33

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over