7-87444459-G-T

Variant names:

• chr7-87444459-G-T
• rs1149222
• NM_000443.4:c.1119+403C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000443.4(ABCB4):​c.1119+403C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 151,916 control chromosomes in the GnomAD database, including 37,124 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (37124 hom., cov: 32)
• Consequence: ABCB4 NM_000443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.706
• Publications: 19 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), ClinGen, Orphanet
• gallbladder disease 1

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.1119+403C>A		intron_variant	Intron 10 of 27	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.1119+403C>A		intron_variant	Intron 10 of 27		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102515 AN: 151798 Hom.: 37133 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.725

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.675 AC: 102521 AN: 151916 Hom.: 37124 Cov.: 32 AF XY: 0.677 AC XY: 50248 AN XY: 74232

African (AFR) AF: 0.389 AC: 16106 AN: 41378

American (AMR) AF: 0.781 AC: 11922 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2647 AN: 3466

East Asian (EAS) AF: 0.610 AC: 3155 AN: 5168

South Asian (SAS) AF: 0.744 AC: 3580 AN: 4812

European-Finnish (FIN) AF: 0.801 AC: 8457 AN: 10554

Middle Eastern (MID) AF: 0.771 AC: 225 AN: 292

European-Non Finnish (NFE) AF: 0.797 AC: 54191 AN: 67956

Other (OTH) AF: 0.720 AC: 1518 AN: 2108

Alfa AF: 0.744 Hom.: 94902

Bravo AF: 0.659

Asia WGS AF: 0.677 AC: 2349 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.18
DANN	Benign	0.40
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs1149222; hg19: chr7-87073775; COSMIC: COSV55942402;