7-87431398-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000443.4(ABCB4):​c.1893+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,614,036 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0028 ( 11 hom. )

Consequence

ABCB4
NM_000443.4 splice_region, intron

Scores

2
Splicing: ADA: 0.03488
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.932
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 7-87431398-A-G is Benign according to our data. Variant chr7-87431398-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr7-87431398-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0018 (274/152302) while in subpopulation SAS AF= 0.00311 (15/4818). AF 95% confidence interval is 0.00252. There are 0 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 11 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCB4NM_000443.4 linkc.1893+6T>C splice_region_variant, intron_variant Intron 15 of 27 ENST00000649586.2 NP_000434.1 P21439-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCB4ENST00000649586.2 linkc.1893+6T>C splice_region_variant, intron_variant Intron 15 of 27 NM_000443.4 ENSP00000496956.2 P21439-2

Frequencies

GnomAD3 genomes
AF:
0.00180
AC:
274
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00980
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00311
Gnomad FIN
AF:
0.000847
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00285
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00230
AC:
579
AN:
251294
Hom.:
2
AF XY:
0.00241
AC XY:
327
AN XY:
135810
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00993
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00310
Gnomad FIN exome
AF:
0.00199
Gnomad NFE exome
AF:
0.00289
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00281
AC:
4106
AN:
1461734
Hom.:
11
Cov.:
31
AF XY:
0.00290
AC XY:
2106
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00972
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00312
Gnomad4 FIN exome
AF:
0.00266
Gnomad4 NFE exome
AF:
0.00295
Gnomad4 OTH exome
AF:
0.00225
GnomAD4 genome
AF:
0.00180
AC:
274
AN:
152302
Hom.:
0
Cov.:
32
AF XY:
0.00177
AC XY:
132
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00980
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00311
Gnomad4 FIN
AF:
0.000847
Gnomad4 NFE
AF:
0.00285
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00299
Hom.:
0
Bravo
AF:
0.00181
EpiCase
AF:
0.00262
EpiControl
AF:
0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ABCB4: BP4 -

not specified Benign:2
Apr 12, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 27, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cholestasis, intrahepatic, of pregnancy, 3 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

ABCB4-related disorder Benign:1
Aug 28, 2024
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive familial intrahepatic cholestasis type 3 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
11
DANN
Benign
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.035
dbscSNV1_RF
Benign
0.21
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs8187798; hg19: chr7-87060714; API