18-57695300-T-C

Variant names:

• chr18-57695300-T-C
• rs319443
• NM_001374385.1:c.811A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001374385.1(ATP8B1):​c.811A>G​(p.Arg271Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R271R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30
• Publications: 21 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 183) in uniprot entity AT8B1_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_001374385.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	NM_001374385.1	MANE Select	c.811A>G	p.Arg271Gly	missense	Exon 10 of 28	NP_001361314.1	O43520
	ATP8B1	NM_005603.6		c.811A>G	p.Arg271Gly	missense	Exon 10 of 28	NP_005594.2	O43520
	ATP8B1	NM_001374386.1		c.661A>G	p.Arg221Gly	missense	Exon 9 of 27	NP_001361315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	ENST00000648908.2	MANE Select	c.811A>G	p.Arg271Gly	missense	Exon 10 of 28	ENSP00000497896.1	O43520
	ATP8B1	ENST00000857621.1		c.811A>G	p.Arg271Gly	missense	Exon 10 of 28	ENSP00000527680.1
	ATP8B1	ENST00000857625.1		c.811A>G	p.Arg271Gly	missense	Exon 11 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.014	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0275)
MVP		0.85
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.82
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs319443; hg19: chr18-55362532;