rs997915795

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000443.4(ABCB4):​c.3819G>C​(p.Gln1273His) 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 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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

14
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.391
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 Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain ABC transporter 2 (size 245) in uniprot entity MDR3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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 pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCB4NM_000443.4 linkc.3819G>C p.Gln1273His missense_variant Exon 28 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.3819G>C p.Gln1273His missense_variant Exon 28 of 28 NM_000443.4 ENSP00000496956.2 P21439-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461762
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
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
Uncertain
0.43
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
.;.;D;.;.
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.87
.;D;D;D;.
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.72
D;D;D;D;D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Uncertain
2.2
.;.;M;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.0
.;D;D;D;D
REVEL
Uncertain
0.64
Sift
Benign
0.039
.;D;D;D;D
Sift4G
Uncertain
0.0090
.;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.37, 0.56, 0.56, 0.37
MutPred
0.53
.;.;Gain of glycosylation at T1283 (P = 0.1902);.;.;
MVP
0.87
MPC
0.44
ClinPred
0.97
D
GERP RS
4.4
Varity_R
0.33
gMVP
0.79

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: chr7-87031433; API