7-87544351-A-T

Variant names:

• chr7-87544351-A-T
• rs1922242
• NM_001348946.2:c.2065-76T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348946.2(ABCB1):​c.2065-76T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,441,452 control chromosomes in the GnomAD database, including 124,490 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 0.42 (13802 hom., cov: 32)
  • Exomes 𝑓: 0.41 (110688 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.960
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.2065-76T>A		intron_variant	Intron 16 of 27	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.2275-76T>A		intron_variant	Intron 20 of 31		NP_001335874.1
ABCB1	NM_000927.5	c.2065-76T>A		intron_variant	Intron 17 of 28		NP_000918.2
ABCB1	NM_001348944.2	c.2065-76T>A		intron_variant	Intron 18 of 29		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.2065-76T>A		intron_variant	Intron 16 of 27	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.2065-76T>A		intron_variant	Intron 17 of 28	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.1873-76T>A		intron_variant	Intron 16 of 27	5		ENSP00000444095.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64486 AN: 151964 Hom.: 13790 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.453

GnomAD4 exome AF: 0.411 AC: 530230 AN: 1289370 Hom.: 110688 AF XY: 0.405 AC XY: 263391 AN XY: 650328

African (AFR) AF: 0.450 AC: 13352 AN: 29648

American (AMR) AF: 0.395 AC: 17123 AN: 43340

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 11587 AN: 24818

East Asian (EAS) AF: 0.328 AC: 12690 AN: 38726

South Asian (SAS) AF: 0.231 AC: 18767 AN: 81138

European-Finnish (FIN) AF: 0.427 AC: 21849 AN: 51192

Middle Eastern (MID) AF: 0.404 AC: 1528 AN: 3780

European-Non Finnish (NFE) AF: 0.427 AC: 411264 AN: 962428

Other (OTH) AF: 0.406 AC: 22070 AN: 54300

GnomAD4 genome AF: 0.424 AC: 64544 AN: 152082 Hom.: 13802 Cov.: 32 AF XY: 0.421 AC XY: 31312 AN XY: 74344

African (AFR) AF: 0.451 AC: 18692 AN: 41474

American (AMR) AF: 0.437 AC: 6682 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1622 AN: 3466

East Asian (EAS) AF: 0.308 AC: 1594 AN: 5168

South Asian (SAS) AF: 0.240 AC: 1159 AN: 4824

European-Finnish (FIN) AF: 0.426 AC: 4504 AN: 10574

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28816 AN: 67980

Other (OTH) AF: 0.449 AC: 949 AN: 2112

Alfa AF: 0.431 Hom.: 1802

Bravo AF: 0.428

Asia WGS AF: 0.287 AC: 1000 AN: 3472

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	-0.89
CADD	Benign	0.76
DANN	Benign	0.28
PhyloP100		-0.96
Mutation Taster		=100/0	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: rs1922242; hg19: chr7-87173667;