rs372685632

Variant names:

• chr7-87462904-C-T
• rs372685632
• NM_000443.4:c.140G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP2 PP5

The NM_000443.4(ABCB4):​c.140G>A​(p.Arg47Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000763 in 1,612,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002062759: PS3:Moderate" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R47R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 5.60
• Publications: 12 publications found

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), Orphanet, ClinGen
• gallbladder disease 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002062759: PS3:Moderate; SCV003440063: Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26256905, 31181191).; SCV002572191: The most pronounced variant effect results in 10%-<30% of normal protein expression in vitro, however protein localization results were not impacted (example, Frider_2015). PMID: 28924228, 31538484; SCV004120131: Functional studies indicated that it may cause reduced protein levels (Frider et al 2015. PubMed ID: 26256905).
• 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, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3.
• PP5: Variant 7-87462904-C-T is Pathogenic according to our data. Variant chr7-87462904-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197144.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	NM_000443.4	MANE Select	c.140G>A	p.Arg47Gln	missense	Exon 4 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.140G>A	p.Arg47Gln	missense	Exon 4 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.140G>A	p.Arg47Gln	missense	Exon 4 of 27	NP_061338.1	P21439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.140G>A	p.Arg47Gln	missense	Exon 4 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.140G>A	p.Arg47Gln	missense	Exon 4 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.140G>A	p.Arg47Gln	missense	Exon 4 of 28	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151696 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000877 AC: 22 AN: 250894 AF XY: 0.0000590

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54 AN XY: 726802

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.000157 AC: 7 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000810 AC: 90 AN: 1111446

Other (OTH) AF: 0.000166 AC: 10 AN: 60358

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151696 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74050

African (AFR) AF: 0.0000242 AC: 1 AN: 41292

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	not provided (5)
1	-	-	ABCB4-related disorder (1)
-	1	-	Inborn genetic diseases (1)
1	-	-	Progressive familial intrahepatic cholestasis (1)
1	-	-	Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.0	N
PhyloP100		5.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.91
MPC		0.82
ClinPred		0.38	T
GERP RS		5.5
Varity_R		0.52
gMVP		0.87
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372685632; hg19: chr7-87092220; COSMIC: COSV55932267;