rs3213619

Variant names:

• chr7-87600877-A-G
• rs3213619
• NM_001348946.2:c.-129T>C

Variant summary

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

The NM_001348946.2(ABCB1):​c.-129T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 152,430 control chromosomes in the GnomAD database, including 211 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 0.051 (210 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1 hom.)
• Consequence: ABCB1 NM_001348946.2 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.417

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.-129T>C		5_prime_UTR_variant	Exon 1 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_000927.5	c.-129T>C		5_prime_UTR_variant	Exon 2 of 29		NP_000918.2
ABCB1	NM_001348945.2	c.134-52T>C		intron_variant	Intron 4 of 31		NP_001335874.1
ABCB1	NM_001348944.2	c.-77-52T>C		intron_variant	Intron 2 of 29		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.-129T>C		5_prime_UTR_variant	Exon 1 of 28	1	NM_001348946.2	ENSP00000478255.1

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7747 AN: 152082 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.0502

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0569

GnomAD4 exome AF: 0.0261 AC: 6 AN: 230 Hom.: 1 Cov.: 0 AF XY: 0.0154 AC XY: 2 AN XY: 130

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.0319

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0511 AC: 7779 AN: 152200 Hom.: 210 Cov.: 32 AF XY: 0.0499 AC XY: 3711 AN XY: 74410

Gnomad4 AFR AF: 0.0851

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.0503

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0418 Hom.: 173

Bravo AF: 0.0514

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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	-0.80
CADD	Benign	8.3
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3213619; hg19: chr7-87230193;