7-87443683-G-C

Variant names:

• chr7-87443683-G-C
• rs863225298
• NM_000443.4:c.1210C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_018849.3(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P404S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCB4 NM_018849.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.84
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018849.3
• 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: 3.5632 (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, 0.965
• 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 VariationId is 242455.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018849.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	NM_000443.4	MANE Select	c.1210C>G	p.Pro404Ala	missense	Exon 11 of 28	NP_000434.1
	ABCB4	NM_018849.3		c.1210C>G	p.Pro404Ala	missense	Exon 11 of 28	NP_061337.1
	ABCB4	NM_018850.3		c.1210C>G	p.Pro404Ala	missense	Exon 11 of 27	NP_061338.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.1210C>G	p.Pro404Ala	missense	Exon 11 of 28	ENSP00000496956.2
	ABCB4	ENST00000265723.8	TSL:1	c.1210C>G	p.Pro404Ala	missense	Exon 11 of 28	ENSP00000265723.4
	ABCB4	ENST00000359206.8	TSL:1	c.1210C>G	p.Pro404Ala	missense	Exon 11 of 28	ENSP00000352135.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33470

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111738

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
1	-	-	Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.96	D
Vest4		0.74
MutPred		0.87		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225298; hg19: chr7-87072999;