rs2230028

Positions:

• chr7-87426860-T-C
• chr7-87426860-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000443.4(ABCB4):​c.1954A>G​(p.Arg652Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,613,710 control chromosomes in the GnomAD database, including 9,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2931 hom., cov: 32)
  • Exomes 𝑓: 0.083 (6722 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.941

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCB4. . Gene score misZ 1.9749 (greater than the threshold 3.09). Trascript score misZ 3.5425 (greater than threshold 3.09). GenCC has associacion of gene with pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030877888).
• BP6: Variant 7-87426860-T-C is Benign according to our data. Variant chr7-87426860-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB4	NM_000443.4	c.1954A>G	p.Arg652Gly	missense_variant	16/28	ENST00000649586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB4	ENST00000649586.2	c.1954A>G	p.Arg652Gly	missense_variant	16/28		NM_000443.4	P1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23204 AN: 151950 Hom.: 2907 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.0998 AC: 25065 AN: 251072 Hom.: 1981 AF XY: 0.0968 AC XY: 13141 AN XY: 135696

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.0899

Gnomad ASJ exome AF: 0.0900

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0737

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0829 AC: 121131 AN: 1461642 Hom.: 6722 Cov.: 33 AF XY: 0.0837 AC XY: 60883 AN XY: 727104

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.0914

Gnomad4 ASJ exome AF: 0.0917

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.0736

Gnomad4 NFE exome AF: 0.0720

Gnomad4 OTH exome AF: 0.0946

GnomAD4 genome AF: 0.153 AC: 23279 AN: 152068 Hom.: 2931 Cov.: 32 AF XY: 0.151 AC XY: 11232 AN XY: 74356

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.0957

Gnomad4 ASJ AF: 0.0950

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.0767

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0865 Hom.: 1498

Bravo AF: 0.160

TwinsUK AF: 0.0782 AC: 290

ALSPAC AF: 0.0703 AC: 271

ESP6500AA AF: 0.343 AC: 1513

ESP6500EA AF: 0.0790 AC: 679

ExAC AF: 0.105 AC: 12793

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.0781

EpiControl AF: 0.0745

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Progressive familial intrahepatic cholestasis type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for PFIC3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Cholestasis, intrahepatic, of pregnancy, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.6
DANN	Benign	0.44
DEOGEN2	Benign	0.25	.;.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.047	.;T;T;T;.
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.31	N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.050	.;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.34	.;T;T;T;T
Sift4G	Benign	0.38	.;T;T;T;T
Polyphen		0.0	B;.;B;B;.
Vest4		0.020, 0.031, 0.019
MPC		0.35
ClinPred		0.00072	T
GERP RS		1.1
Varity_R		0.039
gMVP		0.31

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: rs2230028; hg19: chr7-87056176; COSMIC: COSV55939739;