Genetic Variant NM_001077639.2:c.1192T>C (chr11-114571381-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001077639.2(NXPE4):c.1192T>C(p.Tyr398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,613,528 control chromosomes in the GnomAD database, including 209,998 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 29077 hom., cov: 32)

Exomes 𝑓: 0.49 ( 180921 hom. )

Consequence

NXPE4
NM_001077639.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

Publications

35 publications found

Variant links:

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]

NXPE4 links:

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]

NXPE2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.9848303E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPE4	NM_001077639.2 link	c.1192T>C	p.Tyr398His	missense_variant	Exon 6 of 6	ENST00000375478.4	NP_001071107.1	Q6UWF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NXPE4	ENST00000375478.4 link	c.1192T>C	p.Tyr398His	missense_variant	Exon 6 of 6	1	NM_001077639.2	ENSP00000364627.3		Q6UWF7-1
NXPE4	ENST00000424261.6 link	c.340T>C	p.Tyr114His	missense_variant	Exon 6 of 6	1		ENSP00000401503.2		Q6UWF7-2

Frequencies

GnomAD3 genomes

AF:

0.599

AC:

90939

AN:

151942

Hom.:

29018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.839

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.557

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.666

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.501

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.481

Gnomad OTH

AF:

0.574

GnomAD2 exomes

AF:

0.539

AC:

133332

AN:

247188

AF XY:

0.529

show subpopulations

Gnomad AFR exome

AF:

0.849

Gnomad AMR exome

AF:

0.580

Gnomad ASJ exome

AF:

0.540

Gnomad EAS exome

AF:

0.686

Gnomad FIN exome

AF:

0.492

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.522

GnomAD4 exome

AF:

0.492

AC:

718560

AN:

1461466

Hom.:

180921

Cov.:

AF XY:

0.491

AC XY:

356895

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.857

AC:

28686

AN:

33468

American (AMR)

AF:

0.577

AC:

25804

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

14252

AN:

26124

East Asian (EAS)

AF:

0.630

AC:

24983

AN:

39668

South Asian (SAS)

AF:

0.540

AC:

46540

AN:

86240

European-Finnish (FIN)

AF:

0.492

AC:

26272

AN:

53402

Middle Eastern (MID)

AF:

0.517

AC:

2978

AN:

5760

European-Non Finnish (NFE)

AF:

0.465

AC:

517292

AN:

1111720

Other (OTH)

AF:

0.526

AC:

31753

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

21192

42385

63577

84770

105962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15634

31268

46902

62536

78170

<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:

0.599

AC:

91057

AN:

152062

Hom.:

29077

Cov.:

AF XY:

0.600

AC XY:

44546

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.840

AC:

34841

AN:

41500

American (AMR)

AF:

0.557

AC:

8502

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

1919

AN:

3470

East Asian (EAS)

AF:

0.666

AC:

3442

AN:

5170

South Asian (SAS)

AF:

0.561

AC:

2702

AN:

4820

European-Finnish (FIN)

AF:

0.501

AC:

5281

AN:

10550

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.481

AC:

32662

AN:

67972

Other (OTH)

AF:

0.576

AC:

1216

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1727

3454

5180

6907

8634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.519

Hom.:

72353

Bravo

AF:

0.613

TwinsUK

AF:

0.465

AC:

1725

ALSPAC

AF:

0.443

AC:

1708

ESP6500AA

AF:

0.837

AC:

3195

ESP6500EA

AF:

0.488

AC:

4029

ExAC

AF:

0.540

AC:

65273

Asia WGS

AF:

0.619

AC:

2153

AN:

3476

EpiCase

AF:

0.473

EpiControl

AF:

0.473

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.031

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

8.0e-7

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.7

.;N

PhyloP100

3.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

5.3

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.14

MPC

0.073

ClinPred

0.0024

GERP RS

4.5

Varity_R

0.058

gMVP

0.60

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over