7-87443683-G-C

Position:

• chr7-87443683-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000443.4(ABCB4):​c.1210C>G​(p.Pro404Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,508 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.84

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain ABC transporter 1 (size 236) in uniprot entity MDR3_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) 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, 0.965
• PP5: Variant 7-87443683-G-C is Pathogenic according to our data. Variant chr7-87443683-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242455.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.1210C>G	p.Pro404Ala	missense_variant	11/28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.1210C>G	p.Pro404Ala	missense_variant	11/28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 10, 2024

Variant summary: ABCB4 c.1210C>G (p.Pro404Ala) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251224 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1210C>G has been reported in the literature in an individuals affected with Familial Intrahepatic Cholestasis (Huynh_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31538484). ClinVar contains an entry for this variant (Variation ID: 242455). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.1	L;L;L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.0	.;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.021	.;D;D;D;D
Polyphen		0.96	D;.;P;D;.
Vest4		0.74, 0.70, 0.70, 0.73
MutPred		0.87		Gain of catalytic residue at P404 (P = 0.0491);Gain of catalytic residue at P404 (P = 0.0491);Gain of catalytic residue at P404 (P = 0.0491);Gain of catalytic residue at P404 (P = 0.0491);Gain of catalytic residue at P404 (P = 0.0491);
MVP		0.87
MPC		0.69
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.86
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs863225298; hg19: chr7-87072999;