NM_022437.3:c.-19T>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022437.3(ABCG8):​c.-19T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,549,390 control chromosomes in the GnomAD database, including 104,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11545 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92987 hom.)
• Consequence: ABCG8 NM_022437.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-43839035-T-G is Benign according to our data. Variant chr2-43839035-T-G is described in ClinVar as Benign. ClinVar VariationId is 193450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

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>G		5_prime_UTR	Exon 1 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.-19T>G		5_prime_UTR	Exon 1 of 13	NP_001344250.1	Q9H221-2
	ABCG5	NM_022436.3	MANE Select	c.-356A>C		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>G		5_prime_UTR	Exon 1 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.-19T>G		5_prime_UTR	Exon 1 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.-19T>G		5_prime_UTR	Exon 1 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56881 AN: 151856 Hom.: 11520 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.398 AC: 61687 AN: 154852 AF XY: 0.403

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.852

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.351 AC: 489991 AN: 1397414 Hom.: 92987 Cov.: 33 AF XY: 0.355 AC XY: 244563 AN XY: 689280

African (AFR) AF: 0.396 AC: 12490 AN: 31548

American (AMR) AF: 0.372 AC: 13261 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6008 AN: 25166

East Asian (EAS) AF: 0.852 AC: 30439 AN: 35726

South Asian (SAS) AF: 0.501 AC: 39633 AN: 79134

European-Finnish (FIN) AF: 0.369 AC: 18057 AN: 48920

Middle Eastern (MID) AF: 0.261 AC: 1414 AN: 5416

European-Non Finnish (NFE) AF: 0.323 AC: 348145 AN: 1077914

Other (OTH) AF: 0.355 AC: 20544 AN: 57896

GnomAD4 genome AF: 0.375 AC: 56943 AN: 151976 Hom.: 11545 Cov.: 32 AF XY: 0.383 AC XY: 28420 AN XY: 74288

African (AFR) AF: 0.405 AC: 16800 AN: 41440

American (AMR) AF: 0.363 AC: 5545 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3472

East Asian (EAS) AF: 0.845 AC: 4357 AN: 5154

South Asian (SAS) AF: 0.524 AC: 2518 AN: 4808

European-Finnish (FIN) AF: 0.372 AC: 3937 AN: 10576

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21952 AN: 67928

Other (OTH) AF: 0.358 AC: 756 AN: 2112

Alfa AF: 0.247 Hom.: 864

Bravo AF: 0.371

Asia WGS AF: 0.606 AC: 2107 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Sitosterolemia 1 (2)
-	-	1	Sitosterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.77
DANN	Benign	0.68
PhyloP100		-1.6
PromoterAI		0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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; COSMIC: COSV53211449; COSMIC: COSV53211449;