Genetic Variant ENPP6:p.Ser419Gly (chr4-184091245-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

The NM_153343.4(ENPP6):c.1255A>G(p.Ser419Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,597,070 control chromosomes in the GnomAD database, including 163,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.52 ( 21149 hom., cov: 32)

Exomes 𝑓: 0.44 ( 142559 hom. )

Consequence

ENPP6
NM_153343.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.435

Publications

25 publications found

Variant links:

Genes affected

ENPP6 (HGNC:23409): (ectonucleotide pyrophosphatase/phosphodiesterase 6) Enables glycerophosphocholine cholinephosphodiesterase activity. Involved in choline metabolic process and lipid metabolic process. Located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENPP6 links:

LOC124900826 (HGNC:):

LOC124900826 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a lipid_moiety_binding_region GPI-anchor amidated serine (size 0) in uniprot entity ENPP6_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=4.601098E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP6	NM_153343.4 link	c.1255A>G	p.Ser419Gly	missense_variant	Exon 8 of 8	ENST00000296741.7	NP_699174.1	Q6UWR7
LOC124900826	XR_007058415.1 link	n.2028-852T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP6	ENST00000296741.7 link	c.1255A>G	p.Ser419Gly	missense_variant	Exon 8 of 8	1	NM_153343.4	ENSP00000296741.2		Q6UWR7

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78314

AN:

151948

Hom.:

21107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.672

Gnomad AMI

AF:

0.505

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.424

Gnomad EAS

AF:

0.586

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.488

GnomAD2 exomes

AF:

0.489

AC:

114653

AN:

234540

AF XY:

0.478

show subpopulations

Gnomad AFR exome

AF:

0.686

Gnomad AMR exome

AF:

0.602

Gnomad ASJ exome

AF:

0.411

Gnomad EAS exome

AF:

0.597

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.442

GnomAD4 exome

AF:

0.440

AC:

635253

AN:

1445006

Hom.:

142559

Cov.:

AF XY:

0.439

AC XY:

314764

AN XY:

717058

show subpopulations

African (AFR)

AF:

0.679

AC:

22657

AN:

33376

American (AMR)

AF:

0.590

AC:

25811

AN:

43782

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

10303

AN:

24684

East Asian (EAS)

AF:

0.597

AC:

23668

AN:

39640

South Asian (SAS)

AF:

0.477

AC:

39129

AN:

82076

European-Finnish (FIN)

AF:

0.445

AC:

23266

AN:

52308

Middle Eastern (MID)

AF:

0.412

AC:

2318

AN:

5620

European-Non Finnish (NFE)

AF:

0.418

AC:

461567

AN:

1103746

Other (OTH)

AF:

0.444

AC:

26534

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

20120

40239

60359

80478

100598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14404

28808

43212

57616

72020

<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:

0.516

AC:

78419

AN:

152064

Hom.:

21149

Cov.:

AF XY:

0.519

AC XY:

38599

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.673

AC:

27916

AN:

41498

American (AMR)

AF:

0.555

AC:

8488

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

1470

AN:

3470

East Asian (EAS)

AF:

0.586

AC:

3025

AN:

5166

South Asian (SAS)

AF:

0.491

AC:

2361

AN:

4810

European-Finnish (FIN)

AF:

0.441

AC:

4673

AN:

10590

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.425

AC:

28866

AN:

67936

Other (OTH)

AF:

0.492

AC:

1035

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1939

3878

5818

7757

9696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.453

Hom.:

24950

Bravo

AF:

0.529

TwinsUK

AF:

0.405

AC:

1501

ALSPAC

AF:

0.412

AC:

1589

ESP6500AA

AF:

0.663

AC:

2919

ESP6500EA

AF:

0.419

AC:

3605

ExAC

AF:

0.485

AC:

58789

Asia WGS

AF:

0.546

AC:

1900

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.10

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.046

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.16

MetaRNN

Benign

0.000046

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.46

PhyloP100

-0.43

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.95

REVEL

Benign

0.19

Sift

Benign

0.52

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.021

MPC

0.082

ClinPred

0.0098

GERP RS

-5.0

Varity_R

0.041

gMVP

0.28

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