chr18-57697797-G-T

Variant names:

• chr18-57697797-G-T
• rs515726138
• NM_001374385.1:c.625C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001374385.1(ATP8B1):​c.625C>A​(p.Pro209Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense, splice_region
• Scores: Splicing: ADA: 0.1441
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.75
• Publications: 6 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: Likely_pathogenic. The variant received 8 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, 0.958

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.625C>A	p.Pro209Thr	missense splice_region	Exon 7 of 28	NP_001361314.1	O43520
	ATP8B1	NM_005603.6		c.625C>A	p.Pro209Thr	missense splice_region	Exon 7 of 28	NP_005594.2	O43520
	ATP8B1	NM_001374386.1		c.475C>A	p.Pro159Thr	missense splice_region	Exon 6 of 27	NP_001361315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	ENST00000648908.2	MANE Select	c.625C>A	p.Pro209Thr	missense splice_region	Exon 7 of 28	ENSP00000497896.1	O43520
	ATP8B1	ENST00000857621.1		c.625C>A	p.Pro209Thr	missense splice_region	Exon 7 of 28	ENSP00000527680.1
	ATP8B1	ENST00000857625.1		c.625C>A	p.Pro209Thr	missense splice_region	Exon 8 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251358 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461742 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.22	N
REVEL	Pathogenic	0.76
Sift	Benign	0.39	T
Sift4G	Benign	0.37	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.86		Gain of sheet (P = 0.1208)
MVP		0.94
ClinPred		0.49	T
GERP RS		5.2
Varity_R		0.30
gMVP		0.88
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.010		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: rs515726138; hg19: chr18-55365029;