Genetic Variant ABCB1:p.Ile1145Ile (chr7-87509329-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_001348946.2(ABCB1):c.3435T>C (p.Ile1145Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.484 (AC=781,358) in the gnomAD database across 1,613,756 control chromosomes, including 196,010 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.813. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 26668 hom., cov: 31)

Exomes 𝑓: 0.48 ( 169342 hom. )

Consequence

ABCB1
NM_001348946.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.52

Publications

3153 publications found

Variant links:

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]

ABCB1 Gene-Disease associations (from GenCC):

inflammatory bowel disease 13
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ABCB1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001348946.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -17 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8127 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001348946.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCB1	NM_001348946.2	MANE Select	c.3435T>C	p.Ile1145Ile	synonymous	Exon 26 of 28	NP_001335875.1	A4D1D2
ABCB1	NM_001348945.2		c.3645T>C	p.Ile1215Ile	synonymous	Exon 30 of 32	NP_001335874.1
ABCB1	NM_000927.5		c.3435T>C	p.Ile1145Ile	synonymous	Exon 27 of 29	NP_000918.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.3435T>C	p.Ile1145Ile	synonymous	Exon 26 of 28	ENSP00000478255.1	P08183-1
ABCB1	ENST00000265724.8	TSL:1	c.3435T>C	p.Ile1145Ile	synonymous	Exon 27 of 29	ENSP00000265724.3	P08183-1
ABCB1	ENST00000488737.6	TSL:1	n.1077T>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86843

AN:

151852

Hom.:

26611

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.504

AC:

126736

AN:

251312

AF XY:

0.491

show subpopulations

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 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.:

AF XY:

0.472

AC XY:

342927

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.821

AC:

27480

AN:

33480

American (AMR)

AF:

0.547

AC:

24460

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.648

AC:

16937

AN:

26134

East Asian (EAS)

AF:

0.603

AC:

23932

AN:

39694

South Asian (SAS)

AF:

0.396

AC:

34151

AN:

86252

European-Finnish (FIN)

AF:

0.390

AC:

20825

AN:

53408

Middle Eastern (MID)

AF:

0.551

AC:

3174

AN:

5764

European-Non Finnish (NFE)

AF:

0.461

AC:

512604

AN:

1111936

Other (OTH)

AF:

0.511

AC:

30833

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23155

46309

69464

92618

115773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15438

30876

46314

61752

77190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.572

AC:

86962

AN:

151970

Hom.:

26668

Cov.:

AF XY:

0.569

AC XY:

42247

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.797

AC:

33035

AN:

41442

American (AMR)

AF:

0.569

AC:

8684

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.653

AC:

2264

AN:

3466

East Asian (EAS)

AF:

0.619

AC:

3196

AN:

5164

South Asian (SAS)

AF:

0.413

AC:

1988

AN:

4818

European-Finnish (FIN)

AF:

0.379

AC:

3998

AN:

10554

Middle Eastern (MID)

AF:

0.527

AC:

155

AN:

294

European-Non Finnish (NFE)

AF:

0.469

AC:

31853

AN:

67940

Other (OTH)

AF:

0.600

AC:

1265

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1737

3475

5212

6950

8687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.599

AC:

158578

AN:

264690

Hom.:

50116

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.507

AC:

254296

AN:

501144

Hom.:

66917

Local populations

ABraOM SABE-WGS-1171

AF:

0.585

AC:

1370

AN:

2342

Hom.:

410

ChinaMAP Phase 1

AF:

0.613

Denmark Genome

AF:

0.447

AC:

134

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.577

AC:

7500

AN:

13006

show subpopulations

European American

AF:

0.476

AC:

4097

AN:

8600

African American

AF:

0.772

AC:

3403

AN:

4406

GenomeAsia100K

AF:

0.516

AC:

1794

AN:

3476

show subpopulations

Oceania

AF:

0.365

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.574

AC:

403

AN:

702

Hom.:

116

South-East Asia

AF:

0.603

AC:

417

AN:

692

Hom.:

124

South Asia

AF:

0.421

AC:

609

AN:

1446

Hom.:

129

Africa

AF:

0.861

AC:

179

AN:

208

Hom.:

America

AF:

0.462

AC:

AN:

Hom.:

West Eurasia

AF:

0.474

AC:

108

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.626

AC:

4527

AN:

7232

Qatari Genome

AF:

0.571

AC:

1147

AN:

2010

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.577

AC:

70804

AN:

122784

Hom.:

20462

Turkish Variome

AF:

0.513

AC:

3446

AN:

6722

Hom.:

880

UK10K

AF:

0.464

AC:

3510

AN:

7562

show subpopulations

TwinsUK

AF:

0.460

AC:

1645

AN:

3574

ALSPAC

AF:

0.467

AC:

1799

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.625

AC:

5599

AN:

8960

Hom.:

1778

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

4878 / 11112AF: 0.438985

7571 / 17612AF: 0.429877

BipEx

(Bipolar disorder (including schizoaffective))

12862 / 28420AF: 0.452569

13010 / 28844AF: 0.451047

Epi25

(Epilepsy)

21546 / 41958AF: 0.513514

34280 / 66888AF: 0.512499

SCHEMA

(Schizophrenia)

87858 / 156742AF: 0.560526

143599 / 259250AF: 0.553902

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ABCB1-related disorder (1)

MDR1 POLYMORPHISM (1)

Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.022

(source)

DANN

Benign

0.56

PhyloP100

-2.5

AlphaGenome AVI

Benign

0.0087

(source)

GPN-Star LLR

3.7

(source)

GPN-Star score

-0.57

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over