7-87402199-T-G

Position:

• chr7-87402199-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain ABC transporter 2 (size 245) in uniprot entity MDR3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000443.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCB4. . Gene score misZ 1.9749 (greater than the threshold 3.09). Trascript score misZ 3.5425 (greater than threshold 3.09). GenCC has associacion of gene with pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.3737A>C	p.Gln1246Pro	missense_variant	28/28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.3737A>C	p.Gln1246Pro	missense_variant	28/28		NM_000443.4	ENSP00000496956	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-87031515;