7-87402185-T-G
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000443.4(ABCB4):c.3751A>C(p.Lys1251Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ABCB4
NM_000443.4 missense
NM_000443.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 0.500
Publications
0 publications found
Genes affected
ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]
ABCB4 Gene-Disease associations (from GenCC):
- progressive familial intrahepatic cholestasis type 3Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- gallbladder disease 1Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
- pancreatitisInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM1
In a domain ABC transporter 2 (size 245) in uniprot entity MDR3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000443.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.
BP4
Computational evidence support a benign effect (MetaRNN=0.33912477).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461796Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727202 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461796
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
727202
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5718
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111986
Other (OTH)
AF:
AC:
0
AN:
60382
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
ABCB4-related disorder Uncertain:1
Jan 02, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The ABCB4 c.3751A>C variant is predicted to result in the amino acid substitution p.Lys1251Gln. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Benign
.;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;N;.;.
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
.;N;N;N;N
REVEL
Benign
Sift
Benign
.;T;T;T;T
Sift4G
Benign
.;T;T;T;T
Polyphen
B;.;B;B;.
Vest4
0.14, 0.13, 0.14
MutPred
0.47
.;.;Loss of ubiquitination at K1258 (P = 0.0218);.;.;
MVP
0.80
MPC
0.30
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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