rs119479066
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000405322.8(ABCG5):c.727C>T(p.Arg243Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,613,926 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
ABCG5
ENST00000405322.8 stop_gained
ENST00000405322.8 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.75
Genes affected
ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) The 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 White subfamily. The protein encoded by this gene functions as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-43826429-G-A is Pathogenic according to our data. Variant chr2-43826429-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4977.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCG5 | NM_022436.3 | c.727C>T | p.Arg243Ter | stop_gained | 6/13 | ENST00000405322.8 | NP_071881.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCG5 | ENST00000405322.8 | c.727C>T | p.Arg243Ter | stop_gained | 6/13 | 1 | NM_022436.3 | ENSP00000384513 | P1 | |
ABCG5 | ENST00000486512.5 | n.1639+1554C>T | intron_variant, non_coding_transcript_variant | 1 | ||||||
ABCG5 | ENST00000409962.1 | n.1401+1554C>T | intron_variant, non_coding_transcript_variant | 2 | ||||||
ABCG5 | ENST00000644754.1 | n.1288+1554C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251496Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135922
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727238
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74256
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ABCG5-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2022 | The ABCG5 c.727C>T variant is predicted to result in premature protein termination (p.Arg243*). This variant was reported in the homozygous state in siblings from two families with sitosterolaemia (Fig 2a, Lee et al. 2001. PubMed ID: 11138003; Figure 3, Jamwal et al. 2017. PubMed ID: 29102041). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-44053568-G-A). Nonsense variants in ABCG5 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Sitosterolemia 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at