rs146534033

chr2-43814506-T-Cchr2-43814506-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022436.3(ABCG5):c.1733A>G(p.Asn578Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,608,272 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17862716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG5	NM_022436.3	c.1733A>G	p.Asn578Ser	missense_variant	12/13	ENST00000405322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG5	ENST00000405322.8	c.1733A>G	p.Asn578Ser	missense_variant	12/13	1	NM_022436.3	P1
ABCG5	ENST00000486512.5	n.2254A>G		non_coding_transcript_exon_variant	8/9	1
ABCG5	ENST00000409962.1	n.2016A>G		non_coding_transcript_exon_variant	8/9	2
ABCG5	ENST00000644754.1	n.2117A>G		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000299 AC: 75 AN: 251024 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1455940 Hom.: 1 Cov.: 28 AF XY: 0.000115 AC XY: 83 AN XY: 724704

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74494

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sitosterolemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 578 of the ABCG5 protein (p.Asn578Ser). This variant is present in population databases (rs146534033, gnomAD 0.2%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 29066094). ClinVar contains an entry for this variant (Variation ID: 500473). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 22, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The p.N578S variant (also known as c.1733A>G), located in coding exon 12 of the ABCG5 gene, results from an A to G substitution at nucleotide position 1733. The asparagine at codon 578 is replaced by serine, an amino acid with highly similar properties. This variant was detected in two individuals from a Spanish hypercholesterolemia cohort (Lamiquiz-Moneo I et al. J Clin Lipidol Oct;11:1432-1440.e4). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.50
Sift	Benign	0.19	T;.
Sift4G	Uncertain	0.011	D;.
Polyphen		0.98	D;D
Vest4		0.62
MVP		0.90
MPC		0.37
ClinPred		0.15	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.52
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs146534033; hg19: chr2-44041645;