rs119479066

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

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.75
Variant links:
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]

Genome browser will be placed here

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
ABCG5NM_022436.3 linkuse as main transcriptc.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
ABCG5ENST00000405322.8 linkuse as main transcriptc.727C>T p.Arg243Ter stop_gained 6/131 NM_022436.3 ENSP00000384513 P1Q9H222-1
ABCG5ENST00000486512.5 linkuse as main transcriptn.1639+1554C>T intron_variant, non_coding_transcript_variant 1
ABCG5ENST00000409962.1 linkuse as main transcriptn.1401+1554C>T intron_variant, non_coding_transcript_variant 2
ABCG5ENST00000644754.1 linkuse as main transcriptn.1288+1554C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152050
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000437
AC:
11
AN:
251496
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152050
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingPreventionGenetics, part of Exact SciencesNov 30, 2022The 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 providedliterature onlyOMIMJan 01, 2001- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.94
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.98
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs119479066; hg19: chr2-44053568; API