rs901129455

Variant names:

• chr2-43831963-A-C
• rs901129455
• NM_022436.3:c.386T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-43831963-A-C
• chr2-43831963-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022436.3(ABCG5):​c.386T>G​(p.Phe129Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,418 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F129S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• Publications: 0 publications found

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]

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: Orphanet, ClinGen, Illumina
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.386T>G	p.Phe129Cys	missense	Exon 3 of 13	NP_071881.1	Q9H222-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.386T>G	p.Phe129Cys	missense	Exon 3 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.1038T>G		non_coding_transcript_exon	Exon 2 of 9
	ABCG5	ENST00000882115.1		c.386T>G	p.Phe129Cys	missense	Exon 3 of 13	ENSP00000552174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398418 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689730

African (AFR) AF: 0.00 AC: 0 AN: 31710

American (AMR) AF: 0.00 AC: 0 AN: 35734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35900

South Asian (SAS) AF: 0.00 AC: 0 AN: 79262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079168

Other (OTH) AF: 0.00 AC: 0 AN: 57976

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	-0.080	N
PhyloP100		5.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.50
Sift	Benign	0.16	T
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.60		Loss of stability (P = 0.1763)
MVP		0.92
MPC		0.12
ClinPred		0.81	D
GERP RS		4.3
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.92
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs901129455; hg19: chr2-44059102;