Genetic Variant NM_001374385.1:c.1729A>G (chr18-57674924-T-C) – 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_001374385.1(ATP8B1):c.1729A>G(p.Ile577Val) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,614,232 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 70 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.16

Publications

18 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=0.013537943).

BP6

Variant 18-57674924-T-C is Benign according to our data. Variant chr18-57674924-T-C is described in ClinVar as Benign. ClinVar VariationId is 259816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00211 (322/152344) while in subpopulation EAS AF = 0.0482 (250/5186). AF 95% confidence interval is 0.0433. There are 10 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B1	NM_001374385.1	MANE Select	c.1729A>G	p.Ile577Val	missense	Exon 16 of 28	NP_001361314.1	O43520
ATP8B1	NM_005603.6		c.1729A>G	p.Ile577Val	missense	Exon 16 of 28	NP_005594.2	O43520
ATP8B1	NM_001374386.1		c.1579A>G	p.Ile527Val	missense	Exon 15 of 27	NP_001361315.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B1	ENST00000648908.2	MANE Select	c.1729A>G	p.Ile577Val	missense	Exon 16 of 28	ENSP00000497896.1	O43520
ATP8B1	ENST00000857621.1		c.1729A>G	p.Ile577Val	missense	Exon 16 of 28	ENSP00000527680.1
ATP8B1	ENST00000857625.1		c.1729A>G	p.Ile577Val	missense	Exon 17 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0483

Gnomad SAS

AF:

0.00827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00484

AC:

1216

AN:

251482

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0507

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00200

AC:

2931

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

1588

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0504

AC:

2001

AN:

39698

South Asian (SAS)

AF:

0.00754

AC:

650

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000944

AC:

105

AN:

1112008

Other (OTH)

AF:

0.00233

AC:

141

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

161

323

484

646

807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00211

AC:

322

AN:

152344

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

191

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41594

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0482

AC:

250

AN:

5186

South Asian (SAS)

AF:

0.00849

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000995

Hom.:

Bravo

AF:

0.00204

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00470

AC:

570

Asia WGS

AF:

0.0300

AC:

106

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.73

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.1

PhyloP100

5.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.77

REVEL

Benign

0.26

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.95

Vest4

0.22

MVP

0.69

ClinPred

0.044

GERP RS

4.5

Varity_R

0.080

gMVP

0.47

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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