rs1202283

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 71 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 -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 VariationId is 198082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.504C>T	p.Asn168Asn	synonymous	Exon 6 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.504C>T	p.Asn168Asn	synonymous	Exon 6 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.504C>T	p.Asn168Asn	synonymous	Exon 6 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.504C>T	p.Asn168Asn	synonymous	Exon 6 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.504C>T	p.Asn168Asn	synonymous	Exon 6 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.504C>T	p.Asn168Asn	synonymous	Exon 6 of 28	ENSP00000352135.3	P21439-2

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

GnomAD2 exomes AF: 0.480 AC: 120567 AN: 251264 AF XY: 0.489

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 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

African (AFR) AF: 0.0833 AC: 2790 AN: 33476

American (AMR) AF: 0.434 AC: 19396 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10112 AN: 26122

East Asian (EAS) AF: 0.393 AC: 15601 AN: 39690

South Asian (SAS) AF: 0.442 AC: 38128 AN: 86240

European-Finnish (FIN) AF: 0.637 AC: 34025 AN: 53394

Middle Eastern (MID) AF: 0.437 AC: 2523 AN: 5768

European-Non Finnish (NFE) AF: 0.561 AC: 623410 AN: 1111366

Other (OTH) AF: 0.481 AC: 29017 AN: 60370

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

African (AFR) AF: 0.105 AC: 4341 AN: 41410

American (AMR) AF: 0.489 AC: 7466 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1380 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1968 AN: 5154

South Asian (SAS) AF: 0.443 AC: 2126 AN: 4804

European-Finnish (FIN) AF: 0.651 AC: 6873 AN: 10556

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37665 AN: 67958

Other (OTH) AF: 0.429 AC: 905 AN: 2108

Alfa AF: 0.503 Hom.: 84674

Bravo AF: 0.388

Asia WGS AF: 0.410 AC: 1427 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.545

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Cholestasis, intrahepatic, of pregnancy, 3 (2)
-	-	2	not provided (2)
-	-	2	Progressive familial intrahepatic cholestasis type 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.67
DANN	Benign	0.60
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1202283; hg19: chr7-87082292; COSMIC: COSV55935518;