7-87509329-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001348946.2(ABCB1):c.3435T>C(p.Ile1145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,756 control chromosomes in the GnomAD database, including 196,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26668 hom., cov: 31)
  • Exomes 𝑓: 0.48 (169342 hom.)
• Consequence: ABCB1 NM_001348946.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: -2.52

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-87509329-A-G is Benign according to our data. Variant chr7-87509329-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 225939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87509329-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.3435T>C	p.Ile1145=	synonymous_variant	26/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.3645T>C	p.Ile1215=	synonymous_variant	30/32
ABCB1	NM_000927.5	c.3435T>C	p.Ile1145=	synonymous_variant	27/29
ABCB1	NM_001348944.2	c.3435T>C	p.Ile1145=	synonymous_variant	28/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.3435T>C	p.Ile1145=	synonymous_variant	26/28	1	NM_001348946.2	P1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86843 AN: 151852 Hom.: 26611 Cov.: 31

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.601

GnomAD3 exomes AF: 0.504 AC: 126736 AN: 251312 Hom.: 33677 AF XY: 0.491 AC XY: 66644 AN XY: 135820

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.632

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.475 AC: 694396 AN: 1461786 Hom.: 169342 Cov.: 61 AF XY: 0.472 AC XY: 342927 AN XY: 727204

Gnomad4 AFR exome AF: 0.821

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.396

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.461

Gnomad4 OTH exome AF: 0.511

GnomAD4 genome AF: 0.572 AC: 86962 AN: 151970 Hom.: 26668 Cov.: 31 AF XY: 0.569 AC XY: 42247 AN XY: 74274

Gnomad4 AFR AF: 0.797

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.653

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.600

Alfa AF: 0.497 Hom.: 44976

Bravo AF: 0.599

Asia WGS AF: 0.516 AC: 1794 AN: 3476

EpiCase AF: 0.478

EpiControl AF: 0.477

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ABCB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MDR1 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 26, 2007

- -

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

Non-small cell lung carcinoma Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.022
Dann	Benign	0.56

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: rs1045642; hg19: chr7-87138645; COSMIC: COSV55952233; COSMIC: COSV55952233;