rs752916287

Positions:

• chr7-87411911-C-G
• chr7-87411911-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000443.4(ABCB4):​c.2906G>C​(p.Arg969Pro) 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 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R969H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319

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 transmembrane type-1 2 (size 288) in uniprot entity MDR3_HUMAN there are 25 pathogenic changes around while only 2 benign (93%) in NM_000443.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-87411911-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191220.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=3}.
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39253074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB4	NM_000443.4	c.2906G>C	p.Arg969Pro	missense_variant	23/28	ENST00000649586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB4	ENST00000649586.2	c.2906G>C	p.Arg969Pro	missense_variant	23/28		NM_000443.4	P1
ABCB4	ENST00000265723.8	c.2906G>C	p.Arg969Pro	missense_variant	23/28	1
ABCB4	ENST00000359206.8	c.2906G>C	p.Arg969Pro	missense_variant	23/28	1		P1
ABCB4	ENST00000453593.5	c.2783+1706G>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250890 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461204 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.30	N;N;N
MutationTaster	Benign	0.89	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.27	.;T;T
Sift4G	Benign	0.27	.;T;T
Polyphen		0.87	P;P;P
Vest4		0.58, 0.56
MutPred		0.46		Loss of catalytic residue at R969 (P = 0.011);Loss of catalytic residue at R969 (P = 0.011);Loss of catalytic residue at R969 (P = 0.011);
MVP		0.65
MPC		0.63
ClinPred		0.68	D
GERP RS		3.6
Varity_R		0.53
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752916287; hg19: chr7-87041227;