7-87402199-T-G

Variant names:

• chr7-87402199-T-G
• NM_000443.4:c.3737A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000443.4(ABCB4):​c.3737A>C​(p.Gln1246Pro) 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 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• 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: Likely_pathogenic. The variant received 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.3737A>C	p.Gln1246Pro	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.3737A>C	p.Gln1246Pro	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: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 3 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3737A>C (p.Gln1246Pro) missense variant in ABCB4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln1246Pro variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Gln at position 1246 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gln1246Pro in ABCB4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;.;D;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D;D;.
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.6	.;.;L;.;.
PhyloP100		3.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.0	.;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.029	.;D;D;D;D
Sift4G	Uncertain	0.045	.;D;D;D;D
Polyphen		0.81	P;.;P;P;.
Vest4		0.64, 0.65, 0.66, 0.64
MutPred		0.64		.;.;Loss of ubiquitination at K1258 (P = 0.1435);.;.;
MVP		0.82
MPC		0.58
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.88
Mutation Taster		=39/61	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

hg19: chr7-87031515;