NM_000443.4:c.3819G>C

Variant names:

• chr7-87402117-C-G
• rs997915795
• NM_000443.4:c.3819G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000443.4(ABCB4):​c.3819G>C​(p.Gln1273His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1273Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a domain ABC transporter 2 (size 245) in uniprot entity MDR3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000443.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.3819G>C	p.Gln1273His	missense_variant	Exon 28 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.3819G>C	p.Gln1273His	missense_variant	Exon 28 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727194

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;.;D;.;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	.;D;D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.
PhyloP100		0.39
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	.;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.039	.;D;D;D;D
Sift4G	Uncertain	0.0090	.;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.37, 0.56, 0.56, 0.37
MutPred		0.53		.;.;Gain of glycosylation at T1283 (P = 0.1902);.;.;
MVP		0.87
MPC		0.44
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.79
Mutation Taster		=19/81	disease causing

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: rs997915795; hg19: chr7-87031433;