NM_022436.3:c.293C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_022436.3(ABCG5):c.293C>G(p.Ala98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,581,976 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 12 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 9.21

Publications

16 publications found

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]

ABCG5 links:

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) 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 to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 Gene-Disease associations (from GenCC):

sitosterolemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, ClinGen, Orphanet
sitosterolemia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.028946191).

BP6

Variant 2-43832056-G-C is Benign according to our data. Variant chr2-43832056-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289815.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.002 (304/152280) while in subpopulation AMR AF = 0.00418 (64/15302). AF 95% confidence interval is 0.00336. There are 1 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022436.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	NM_022436.3	MANE Select	c.293C>G	p.Ala98Gly	missense	Exon 3 of 13	NP_071881.1	Q9H222-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.293C>G	p.Ala98Gly	missense	Exon 3 of 13	ENSP00000384513.2	Q9H222-1
ABCG5	ENST00000486512.5	TSL:1	n.945C>G		non_coding_transcript_exon	Exon 2 of 9
ABCG5	ENST00000882115.1		c.293C>G	p.Ala98Gly	missense	Exon 3 of 13	ENSP00000552174.1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00237

AC:

463

AN:

194998

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00214

AC:

3061

AN:

1429696

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

1542

AN XY:

707604

show subpopulations

African (AFR)

AF:

0.000334

AC:

AN:

32952

American (AMR)

AF:

0.00274

AC:

110

AN:

40076

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

271

AN:

25432

East Asian (EAS)

AF:

0.00

AC:

AN:

38340

South Asian (SAS)

AF:

0.00380

AC:

309

AN:

81316

European-Finnish (FIN)

AF:

0.00128

AC:

AN:

50094

Middle Eastern (MID)

AF:

0.00960

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00190

AC:

2079

AN:

1096598

Other (OTH)

AF:

0.00274

AC:

162

AN:

59160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

227

455

682

910

1137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152280

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41566

American (AMR)

AF:

0.00418

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68010

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00234

AC:

ExAC

AF:

0.00169

AC:

202

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Sitosterolemia 1 (2)

ABCG5-related disorder (1)

Cardiovascular phenotype (1)

Hyperuricemic nephropathy, familial juvenile type 4 (1)

Sitosterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.029

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

PhyloP100

9.2

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.018

Polyphen

0.98

Vest4

0.72

MVP

0.92

MPC

0.34

ClinPred

0.065

GERP RS

5.4

PromoterAI

-0.24

Neutral

(source)

Varity_R

0.79

gMVP

0.74

Mutation Taster

=195/105

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over