rs3842

Positions:

• chr7-87504050-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348946.2(ABCB1):​c.*193A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 651,800 control chromosomes in the GnomAD database, including 8,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (1917 hom., cov: 32)
  • Exomes 𝑓: 0.15 (6416 hom.)
• Consequence: ABCB1 NM_001348946.2 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.22

Genes affected

ABCB1 (HGNC:40): (ATP binding cassette subfamily B member 1) The membrane-associated 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 MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.*193A>G		3_prime_UTR_variant	28/28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_000927.5	c.*193A>G		3_prime_UTR_variant	29/29		NP_000918.2
ABCB1	NM_001348944.2	c.*193A>G		3_prime_UTR_variant	30/30		NP_001335873.1
ABCB1	NM_001348945.2	c.*193A>G		3_prime_UTR_variant	32/32		NP_001335874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.*193A>G		3_prime_UTR_variant	28/28	1	NM_001348946.2	ENSP00000478255	P1
ABCB1	ENST00000265724.8	c.*193A>G		3_prime_UTR_variant	29/29	1		ENSP00000265724	P1
ABCB1	ENST00000488737.6	n.1678A>G		non_coding_transcript_exon_variant	9/9	1
ABCB1	ENST00000543898.5	c.*193A>G		3_prime_UTR_variant	28/28	5		ENSP00000444095

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23934 AN: 152026 Hom.: 1916 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.155 AC: 77370 AN: 499656 Hom.: 6416 Cov.: 6 AF XY: 0.155 AC XY: 40709 AN XY: 262136

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.157 AC: 23948 AN: 152144 Hom.: 1917 Cov.: 32 AF XY: 0.157 AC XY: 11686 AN XY: 74386

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.151

Alfa AF: 0.144 Hom.: 1774

Bravo AF: 0.159

Asia WGS AF: 0.212 AC: 737 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.26
DANN	Benign	0.43

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

LitVar

Other links and lift over

dbSNP: rs3842; hg19: chr7-87133366; COSMIC: COSV105051408; COSMIC: COSV105051408;