rs58238559

chr7-87452957-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000443.4(ABCB4):c.523A>G(p.Thr175Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,613,900 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T175M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0094 (134 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 5.09

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ABCB4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011848539).
• BP6: Variant 7-87452957-T-C is Benign according to our data. Variant chr7-87452957-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 13691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87452957-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB4	NM_000443.4	c.523A>G	p.Thr175Ala	missense_variant	6/28	ENST00000649586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB4	ENST00000649586.2	c.523A>G	p.Thr175Ala	missense_variant	6/28		NM_000443.4	P1

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1385 AN: 152188 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.0113 AC: 2847 AN: 251274 Hom.: 28 AF XY: 0.0117 AC XY: 1595 AN XY: 135796

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00828

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.00936 AC: 13680 AN: 1461594 Hom.: 134 Cov.: 29 AF XY: 0.00964 AC XY: 7007 AN XY: 727118

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00781

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.00862

Gnomad4 OTH exome AF: 0.00760

GnomAD4 genome AF: 0.00909 AC: 1385 AN: 152306 Hom.: 12 Cov.: 31 AF XY: 0.0103 AC XY: 768 AN XY: 74470

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00909 Hom.: 10

Bravo AF: 0.00598

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0106 AC: 1288

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 110/13006=8.45%; Frequency in ESP (EA): 103/8600=1.19% -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	This variant is associated with the following publications: (PMID: 23022423, 26474921, 28776642, 25888430, 26153658, 20163776, 23533021, 25333069, 22331132, 11313316, 27884173, 28176361, 28924228, 29761167, 31335238, 31538484) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ABCB4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Progressive familial intrahepatic cholestasis type 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Low phospholipid associated cholelithiasis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2001

- -

Cholestasis, intrahepatic, of pregnancy, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.49	T
Polyphen		0.84	P;.;P;P;.
Vest4		0.32, 0.48, 0.47, 0.23
MPC		0.78
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.78
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs58238559; hg19: chr7-87082273; COSMIC: COSV55941178;