Genetic Variant ATP8B1:p.Ser580Asn (chr18-57674914-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005603.6(ATP8B1):c.1739G>A(p.Ser580Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,236 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 41 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 32 hom. )

Consequence

ATP8B1
NM_005603.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.937

Publications

5 publications found

Variant links:

Genes affected

ATP8B1 (HGNC:3706): (ATPase phospholipid transporting 8B1) This gene encodes a member of the P-type cation transport ATPase family, which belongs to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Mutations in this gene may result in progressive familial intrahepatic cholestasis type 1 and in benign recurrent intrahepatic cholestasis. [provided by RefSeq, Jul 2008]

ATP8B1 links:

ATP8B1-AS1 (HGNC:56042): (ATP8B1 antisense RNA 1)

ATP8B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046786964).

BP6

Variant 18-57674914-C-T is Benign according to our data. Variant chr18-57674914-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 327484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152350) while in subpopulation AFR AF = 0.0424 (1762/41584). AF 95% confidence interval is 0.0407. There are 41 homozygotes in GnomAd4. There are 853 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005603.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8B1	NM_001374385.1	MANE Select	c.1739G>A	p.Ser580Asn	missense	Exon 16 of 28	NP_001361314.1
ATP8B1	NM_005603.6		c.1739G>A	p.Ser580Asn	missense	Exon 16 of 28	NP_005594.2
ATP8B1	NM_001374386.1		c.1589G>A	p.Ser530Asn	missense	Exon 15 of 27	NP_001361315.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8B1	ENST00000648908.2	MANE Select	c.1739G>A	p.Ser580Asn	missense	Exon 16 of 28	ENSP00000497896.1
ATP8B1	ENST00000857621.1		c.1739G>A	p.Ser580Asn	missense	Exon 16 of 28	ENSP00000527680.1
ATP8B1	ENST00000857625.1		c.1739G>A	p.Ser580Asn	missense	Exon 17 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1823

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00319

AC:

802

AN:

251484

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00116

AC:

1698

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

682

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0429

AC:

1435

AN:

33480

American (AMR)

AF:

0.00199

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1112006

Other (OTH)

AF:

0.00242

AC:

146

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0120

AC:

1829

AN:

152350

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

853

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0424

AC:

1762

AN:

41584

American (AMR)

AF:

0.00327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00440

Hom.:

Bravo

AF:

0.0132

ESP6500AA

AF:

0.0397

AC:

175

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00384

AC:

466

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

0.11

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.94

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.65

REVEL

Benign

0.18

Sift

Benign

0.49

Sift4G

Benign

0.49

Polyphen

0.84

Vest4

0.19

MVP

0.82

ClinPred

0.030

GERP RS

5.6

Varity_R

0.13

gMVP

0.48

Mutation Taster

=99/1

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