chr7-87443686-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000443.4(ABCB4):​c.1207T>C​(p.Tyr403His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ABCB4
NM_000443.4 missense

Scores

14
3
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.50
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a domain ABC transporter 1 (size 236) in uniprot entity MDR3_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_000443.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCB4. . Gene score misZ: 1.9749 (greater than the threshold 3.09). Trascript score misZ: 3.5425 (greater than threshold 3.09). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 7-87443686-A-G is Pathogenic according to our data. Variant chr7-87443686-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13695.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCB4NM_000443.4 linkc.1207T>C p.Tyr403His missense_variant 11/28 ENST00000649586.2 NP_000434.1 P21439-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCB4ENST00000649586.2 linkc.1207T>C p.Tyr403His missense_variant 11/28 NM_000443.4 ENSP00000496956.2 P21439-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 3 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 06, 1998- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
.;.;D;.;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
.;T;T;T;.
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;M;M;M;M
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.4
.;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D
Polyphen
0.86
P;.;P;P;.
Vest4
0.89, 0.86, 0.88, 0.90
MutPred
0.88
Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);
MVP
0.92
MPC
0.99
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.89
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918443; hg19: chr7-87073002; API