7-87440230-T-C

Variant names:

• chr7-87440230-T-C
• rs375315619
• NM_000443.4:c.1529A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3 PP2 PP5 BP4

The NM_000443.4(ABCB4):​c.1529A>G​(p.Asn510Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001155111: PS3:Supporting" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N510D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:2
• Conservation: PhyloP100: 5.12
• Publications: 16 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), Orphanet, ClinGen
• gallbladder disease 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001155111: PS3:Supporting; SCV003263803: Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26474921).; SCV002598623: At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability (Delaunay_2016).; SCV004116808: Functional assays in the Delaunay study indicated the p.Asn510Ser change reduced protein stability. PMID:26474921
• 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 pancreatitis, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3.
• PP5: Variant 7-87440230-T-C is Pathogenic according to our data. Variant chr7-87440230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291252.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25034124). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000443.4. 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.1529A>G	p.Asn510Ser	missense	Exon 13 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.1529A>G	p.Asn510Ser	missense	Exon 13 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.1529A>G	p.Asn510Ser	missense	Exon 13 of 27	NP_061338.1	P21439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.1529A>G	p.Asn510Ser	missense	Exon 13 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.1529A>G	p.Asn510Ser	missense	Exon 13 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.1529A>G	p.Asn510Ser	missense	Exon 13 of 28	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251250 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461832 Hom.: 1 Cov.: 33 AF XY: 0.000237 AC XY: 172 AN XY: 727214

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

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000172 AC: 191 AN: 1111982

Other (OTH) AF: 0.000348 AC: 21 AN: 60392

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74510

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	2	-	not provided (6)
4	-	-	Progressive familial intrahepatic cholestasis type 3 (4)
2	-	-	Cholestasis, intrahepatic, of pregnancy, 3 (2)
1	-	-	ABCB4-related disorder (1)
1	-	-	Progressive familial intrahepatic cholestasis (1)
1	-	-	Progressive familial intrahepatic cholestasis type 1 (1)
1	-	-	Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.38	N
PhyloP100		5.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.86	P
Vest4		0.70
MVP		0.88
MPC		0.58
ClinPred		0.31	T
GERP RS		2.1
Varity_R		0.92
gMVP		0.75
Mutation Taster		=60/40	disease causing (ClinVar)

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

dbSNP: rs375315619; hg19: chr7-87069546;