NM_000443.4:c.3608C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000443.4(ABCB4):​c.3608C>T​(p.Ser1203Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

16
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

1 publications found
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]
ABCB4 Gene-Disease associations (from GenCC):
  • progressive familial intrahepatic cholestasis type 3
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
  • gallbladder disease 1
    Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
  • pancreatitis
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCB4NM_000443.4 linkc.3608C>T p.Ser1203Leu missense_variant Exon 27 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.3608C>T p.Ser1203Leu missense_variant Exon 27 of 28 NM_000443.4 ENSP00000496956.2 P21439-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000795
AC:
2
AN:
251444
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461840
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
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:
0.00000270
AC:
3
AN:
1111966
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.95
.;.;D;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;D;D;D;.
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Pathogenic
3.7
.;.;H;.;.
PhyloP100
10
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.2
.;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.85, 0.81, 0.88, 0.84
MutPred
0.83
.;.;Loss of disorder (P = 0.028);.;.;
MVP
0.92
MPC
0.90
ClinPred
1.0
D
GERP RS
5.4
PromoterAI
-0.023
Neutral
Varity_R
0.97
gMVP
0.89
Mutation Taster
=2/98
disease causing

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

Other links and lift over

dbSNP: rs748842753; hg19: chr7-87032476; API