7-87408180-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000443.4(ABCB4):​c.3136C>G​(p.Arg1046Gly) 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 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

7
7
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.00
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity MDR3_HUMAN
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 pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCB4NM_000443.4 linkc.3136C>G p.Arg1046Gly missense_variant Exon 25 of 28 ENST00000649586.2 NP_000434.1 P21439-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCB4ENST00000649586.2 linkc.3136C>G p.Arg1046Gly missense_variant Exon 25 of 28 NM_000443.4 ENSP00000496956.2 P21439-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461870
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727244
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
.;.;D;.;.
Eigen
Benign
0.050
Eigen_PC
Benign
-0.0014
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
.;D;D;D;.
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Benign
1.4
L;.;L;L;.
PrimateAI
Benign
0.37
T
PROVEAN
Pathogenic
-6.7
.;D;D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
.;D;D;D;D
Sift4G
Uncertain
0.022
.;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.59, 0.58, 0.59
MutPred
0.87
Loss of catalytic residue at R1046 (P = 0.0749);.;Loss of catalytic residue at R1046 (P = 0.0749);Loss of catalytic residue at R1046 (P = 0.0749);.;
MVP
0.84
MPC
0.99
ClinPred
0.99
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.67
gMVP
0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-87037496; API