rs1202283

Variant names:

• chr7-87452976-G-A
• rs1202283
• NM_000443.4:c.504C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000443.4(ABCB4):​c.504C>T​(p.Asn168Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 1,613,056 control chromosomes in the GnomAD database, including 228,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (16457 hom., cov: 31)
  • Exomes 𝑓: 0.53 (211967 hom.)
• Consequence: ABCB4 NM_000443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.744

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-87452976-G-A is Benign according to our data. Variant chr7-87452976-G-A is described in ClinVar as [Benign]. Clinvar id is 198082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87452976-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.744 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.504C>T	p.Asn168Asn	synonymous_variant	Exon 6 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.504C>T	p.Asn168Asn	synonymous_variant	Exon 6 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63467 AN: 151800 Hom.: 16462 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.430

GnomAD3 exomes AF: 0.480 AC: 120567 AN: 251264 Hom.: 31250 AF XY: 0.489 AC XY: 66386 AN XY: 135792

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.371

Gnomad SAS exome AF: 0.439

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.530 AC: 775002 AN: 1461138 Hom.: 211967 Cov.: 51 AF XY: 0.529 AC XY: 384772 AN XY: 726898

Gnomad4 AFR exome AF: 0.0833

Gnomad4 AMR exome AF: 0.434

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.393

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.561

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.418 AC: 63447 AN: 151918 Hom.: 16457 Cov.: 31 AF XY: 0.422 AC XY: 31368 AN XY: 74268

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.651

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.429

Alfa AF: 0.514 Hom.: 44979

Bravo AF: 0.388

Asia WGS AF: 0.410 AC: 1427 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.545

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cholestasis, intrahepatic, of pregnancy, 3 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive familial intrahepatic cholestasis type 3 Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.67
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1202283; hg19: chr7-87082292; COSMIC: COSV55935518;