2-43839035-T-A

Variant names:

• chr2-43839035-T-A
• rs3806471
• NM_022437.3:c.-19T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022437.3(ABCG8):​c.-19T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,398,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (1 hom.)
• Consequence: ABCG8 NM_022437.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 24 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• sitosterolemia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022437.3. 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
	ABCG8	NM_022437.3	MANE Select	c.-19T>A		5_prime_UTR	Exon 1 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.-19T>A		5_prime_UTR	Exon 1 of 13	NP_001344250.1	Q9H221-2
	ABCG5	NM_022436.3	MANE Select	c.-356A>T		upstream_gene	N/A	NP_071881.1	Q9H222-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.-19T>A		5_prime_UTR	Exon 1 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.-19T>A		5_prime_UTR	Exon 1 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.-19T>A		5_prime_UTR	Exon 1 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000258 AC: 4 AN: 154852 AF XY: 0.0000366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398256 Hom.: 1 Cov.: 33 AF XY: 0.0000130 AC XY: 9 AN XY: 689668

African (AFR) AF: 0.00 AC: 0 AN: 31576

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078634

Other (OTH) AF: 0.00 AC: 0 AN: 57930

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 864

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.75
DANN	Benign	0.57
PhyloP100		-1.6
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3806471; hg19: chr2-44066174;