rs121909103

chr18-57661282-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_001374385.1(ATP8B1):c.2599C>T(p.Arg867Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.88

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]

(HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-57661281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 871594.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, ATP8B1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 18-57661282-G-A is Pathogenic according to our data. Variant chr18-57661282-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7272.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.2599C>T	p.Arg867Cys	missense_variant	22/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.683-6724G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.2599C>T	p.Arg867Cys	missense_variant	22/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+19230G>A		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.664-6724G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cholestasis, intrahepatic, of pregnancy, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.93		Loss of MoRF binding (P = 0.019);Loss of MoRF binding (P = 0.019);
MVP		0.97
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.80
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs121909103; hg19: chr18-55328514;