7-87431528-C-T

Variant names:

• chr7-87431528-C-T
• rs45575636
• NM_000443.4:c.1769G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1 PP2 PP3 BP4_Strong BP6 BS1 BS2

The NM_000443.4(ABCB4):​c.1769G>A​(p.Arg590Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,614,056 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (41 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:11 B:3 O:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Benign. Variant got -9 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
• 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: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021850199).
• BP6: Variant 7-87431528-C-T is Benign according to our data. Variant chr7-87431528-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13697.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=11, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00604 (920/152262) while in subpopulation NFE AF= 0.00767 (522/68014). AF 95% confidence interval is 0.00713. There are 4 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.1769G>A	p.Arg590Gln	missense_variant	Exon 15 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.1769G>A	p.Arg590Gln	missense_variant	Exon 15 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152144 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00767

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00449 AC: 1127 AN: 251094 Hom.: 4 AF XY: 0.00448 AC XY: 608 AN XY: 135680

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00677 AC: 9892 AN: 1461794 Hom.: 41 Cov.: 31 AF XY: 0.00654 AC XY: 4755 AN XY: 727210

Gnomad4 AFR exome AF: 0.00559

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00804

Gnomad4 OTH exome AF: 0.00613

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152262 Hom.: 4 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74432

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00767

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00678 Hom.: 35

Bravo AF: 0.00663

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00418 AC: 507

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:11 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 590 of the ABCB4 protein (p.Arg590Gln). This variant is present in population databases (rs45575636, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of ABCB4-related conditions (PMID: 18482588, 21119540, 28733223, 31538484). ClinVar contains an entry for this variant (Variation ID: 13697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCB4 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 21, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP2 -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB4: BS2 -

Jul 18, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with ABCB4-related disorders in several individuals who were heterozygous for R590Q alone, homozygous for R590Q, or heterozygous for R590Q and another variant in the ABCB4 gene (Degiorgio et al., 2007; Ziol et al., 2008; Colombo et al., 2011; Poupon et al., 2013; Degiorgio et al., 2015; Lourebam et al., 2021; Almes et al., 2022; Nayagam et al., 2022; Vitale et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 22995991, 26324191, 18083082, 27825922, 31127640, 22675952, 25882097, 21119540, 23533021, 25807286, 28776642, 28924228, 28587926, 28765628, 27936482, 19584064, 29761167, 28733223, 31538484, 32893960, 17726488, Jarasvaraparn-2021[CaseReport], Lourembam-2021[CaseReport], 34662886, 35894240, 34942279, 35626323, 36982896, 18482588) -

Apr 10, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cholestasis, intrahepatic, of pregnancy, 3 Pathogenic:1 Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

May 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCB4 c.1769G>A (p.Arg590Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0045 in 251094 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is benign. c.1769G>A has been reported in the literature among individuals with ABCB4-related conditions such as Anicteric Cholestasis, low phospholipid-associated cholelithiasis (LPAC), Progressive familial intrahepatic cholestasis (example, Ziol_2008, Tuan Huynh_2019, Colombo_2011, Droge_2017). These data do not allow any conclusion about variant significance. At-least one co-occurrence in cis with another presumably pathogenic variant(s) has been reported (Colombo_2011, ABCB4 c.2284G>T, p.G762X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Low phospholipid associated cholelithiasis Pathogenic:1 Uncertain:1

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 1 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 3 Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 Uncertain:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCB4-related disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	.;D;D;D;.
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0020	.;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.85, 0.80, 0.85, 0.86
MVP		0.87
MPC		1.0
ClinPred		0.039	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs45575636; hg19: chr7-87060844; COSMIC: COSV99052096; COSMIC: COSV99052096;