Genetic Variant ATP8B4:p.Phe436Leu (chr15-49934162-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_024837.4(ATP8B4):c.1308C>G(p.Phe436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,610,552 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 30 hom., cov: 32)

Exomes 𝑓: 0.015 ( 245 hom. )

Consequence

ATP8B4
NM_024837.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

15 publications found

Variant links:

Genes affected

ATP8B4 (HGNC:13536): (ATPase phospholipid transporting 8B4 (putative)) This gene encodes a member of the cation transport ATPase (P-type) family and type IV subfamily. The encoded protein is involved in phospholipid transport in the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ATP8B4 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.004249096).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.014 (2128/152134) while in subpopulation NFE AF = 0.0184 (1248/67968). AF 95% confidence interval is 0.0175. There are 30 homozygotes in GnomAd4. There are 1110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024837.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8B4	NM_024837.4	MANE Select	c.1308C>G	p.Phe436Leu	missense	Exon 15 of 28	NP_079113.2
ATP8B4	NR_073596.2		n.1549C>G		non_coding_transcript_exon	Exon 16 of 28
ATP8B4	NR_073597.2		n.1461C>G		non_coding_transcript_exon	Exon 15 of 27

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B4	ENST00000284509.11	TSL:5 MANE Select	c.1308C>G	p.Phe436Leu	missense	Exon 15 of 28	ENSP00000284509.6	Q8TF62
ATP8B4	ENST00000557955.5	TSL:1	n.1308C>G		non_coding_transcript_exon	Exon 15 of 27	ENSP00000453690.1	H0YMP8
ATP8B4	ENST00000558906.5	TSL:1	n.*1027C>G		non_coding_transcript_exon	Exon 16 of 28	ENSP00000452956.1	H0YLJ1

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2129

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00643

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0535

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0135

AC:

3341

AN:

247600

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.00398

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0489

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.0149

AC:

21675

AN:

1458418

Hom.:

245

Cov.:

AF XY:

0.0147

AC XY:

10635

AN XY:

725504

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

33200

American (AMR)

AF:

0.00429

AC:

189

AN:

44076

Ashkenazi Jewish (ASJ)

AF:

0.0123

AC:

321

AN:

26000

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39618

South Asian (SAS)

AF:

0.00182

AC:

156

AN:

85720

European-Finnish (FIN)

AF:

0.0483

AC:

2575

AN:

53262

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0159

AC:

17645

AN:

1110556

Other (OTH)

AF:

0.0120

AC:

720

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

1143

2286

3428

4571

5714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.0140

AC:

2128

AN:

152134

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1110

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41528

American (AMR)

AF:

0.00642

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0535

AC:

567

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0184

AC:

1248

AN:

67968

Other (OTH)

AF:

0.0109

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0138

Hom.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0153

AC:

131

ExAC

AF:

0.0134

AC:

1624

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

0.0065

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

PhyloP100

1.6

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.33

Sift

Benign

0.091

Sift4G

Benign

0.24

Polyphen

0.94

Vest4

0.14

MutPred

0.34

Loss of loop (P = 0.0374)

MPC

0.058

ClinPred

0.069

GERP RS

3.3

Varity_R

0.44

gMVP

0.44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over