rs121918442

Variant names:

• chr7-87406293-G-A
• rs121918442
• NM_000443.4:c.3481C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-87406293-G-A
• chr7-87406293-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP2 PP3_Strong PP5

The NM_000443.4(ABCB4):​c.3481C>T​(p.Pro1161Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,016 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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 9.87
• Publications: 10 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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 gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 7-87406293-G-A is Pathogenic according to our data. Variant chr7-87406293-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13692.

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.3481C>T	p.Pro1161Ser	missense	Exon 26 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.3502C>T	p.Pro1168Ser	missense	Exon 26 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.3340C>T	p.Pro1114Ser	missense	Exon 25 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.3481C>T	p.Pro1161Ser	missense	Exon 26 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.3502C>T	p.Pro1168Ser	missense	Exon 26 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.3481C>T	p.Pro1161Ser	missense	Exon 26 of 28	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251160 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727214

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111924

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74422

African (AFR) AF: 0.0000241 AC: 1 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	not provided (3)
1	-	-	Low phospholipid associated cholelithiasis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.93	P
Vest4		0.92
MVP		0.94
MPC		0.96
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.88
Mutation Taster		=0/100	disease causing

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: rs121918442; hg19: chr7-87035609;