rs119480069

chr2-43824071-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_022436.3(ABCG5):c.1166G>A(p.Arg389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.50

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]

DYNC2LI1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 21) in uniprot entity ABCG5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022436.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-43824071-C-T is Pathogenic according to our data. Variant chr2-43824071-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43824071-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-43824071-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.18254992).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG5	NM_022436.3	c.1166G>A	p.Arg389His	missense_variant	9/13	ENST00000405322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG5	ENST00000405322.8	c.1166G>A	p.Arg389His	missense_variant	9/13	1	NM_022436.3	P1
ABCG5	ENST00000486512.5	n.1687G>A		non_coding_transcript_exon_variant	5/9	1
ABCG5	ENST00000409962.1	n.1449G>A		non_coding_transcript_exon_variant	5/9	2
ABCG5	ENST00000644754.1	n.1550G>A		non_coding_transcript_exon_variant	6/10

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251474 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00154

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sitosterolemia 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2021	PS3, PS4, PM3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 08, 2022	- -

Sitosterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCG5 protein (p.Arg389His). This variant is present in population databases (rs119480069, gnomAD 0.2%). This missense change has been observed in individual(s) with sitosterolemia (PMID: 11138003, 15375183, 20521169, 20543520, 25665839, 28203044, 28771437, 30985648, 31060161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Asian ancestry (PMID: 15375183, 30985648). ClinVar contains an entry for this variant (Variation ID: 4980). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The p.R389H variant (also known as c.1166G>A), located in coding exon 9 of the ABCG5 gene, results from a G to A substitution at nucleotide position 1166. The arginine at codon 389 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in the homozygous and compound heterozygous states in several individuals and families affected with sitosterolemia, being reported as a common cause of disease in Asian populations (Lee MH et al. Nat Genet, 2001 Jan;27:79-83; Wang J et al. J Lipid Res, 2004 Dec;45:2361-7; Niu DM et al. J Inherit Metab Dis, 2010 Aug;33:437-43; Tada H et al. JIMD Rep, 2015 Feb;21:115-22; Ono S et al. Clin Pediatr Endocrinol, 2017 Jan;26:17-23; Yagasaki H et al. J Pediatr Endocrinol Metab, 2017 Aug;30:1007-1011; Huang D et al. Medicine (Baltimore), 2019 Apr;98:e15013; Nomura A et al. Circ Genom Precis Med, 2020 10;13:417-423; Yamada Y et al. CJC Open, 2021 Aug;3:1085-1088). An in vitro study suggested this alteration may impact protein function (Graf GA et al. J Biol Chem, 2004 Jun;279:24881-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.65
Sift	Benign	0.095	T;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.95
MVP		0.92
MPC		0.46
ClinPred		0.31	T
GERP RS		5.9
Varity_R		0.56
gMVP		0.88

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: rs119480069; hg19: chr2-44051210;