7-87431528-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R590P) has been classified as Uncertain significance.

• 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:4 O:1
• Conservation: PhyloP100: 7.86
• Publications: 36 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: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL, 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 VariationId is 13697.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD,AR,AD gene

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.1769G>A	p.Arg590Gln	missense	Exon 15 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.1769G>A	p.Arg590Gln	missense	Exon 15 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.1769G>A	p.Arg590Gln	missense	Exon 15 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.1769G>A	p.Arg590Gln	missense	Exon 15 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.1769G>A	p.Arg590Gln	missense	Exon 15 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.1769G>A	p.Arg590Gln	missense	Exon 15 of 28	ENSP00000352135.3	P21439-2

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

GnomAD2 exomes AF: 0.00449 AC: 1127 AN: 251094 AF XY: 0.00448

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 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

African (AFR) AF: 0.00559 AC: 187 AN: 33470

American (AMR) AF: 0.00541 AC: 242 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86250

European-Finnish (FIN) AF: 0.00217 AC: 116 AN: 53420

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00804 AC: 8940 AN: 1111946

Other (OTH) AF: 0.00613 AC: 370 AN: 60390

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

African (AFR) AF: 0.00585 AC: 243 AN: 41558

American (AMR) AF: 0.00725 AC: 111 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00767 AC: 522 AN: 68014

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00666 Hom.: 41

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
1	1	1	Cholestasis, intrahepatic, of pregnancy, 3 (3)
-	2	1	not specified (3)
1	1	-	Low phospholipid associated cholelithiasis (2)
-	1	1	Progressive familial intrahepatic cholestasis type 3 (2)
-	1	-	Progressive familial intrahepatic cholestasis type 1 (1)
-	1	-	Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 (1)
-	-	-	ABCB4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.87
MPC		1.0
ClinPred		0.039	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.83
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

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