7-87509329-A-G

Variant names:

• chr7-87509329-A-G
• rs1045642
• NM_001348946.2:c.3435T>C
• ABCB1 p.Ile1145Ile

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.52
• Publications: 1 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]

ABCB1 Gene-Disease associations (from GenCC):

• inflammatory bowel disease 13

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		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

Sel.	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	Prot: NP_001335875.1 UniProt:
	ABCB1 NM_001348945.2		c.3645T>C p.Ile1215Ile	synonymous	Exon 30 of 32	Prot: NP_001335874.1
	ABCB1 NM_000927.5		c.3435T>C p.Ile1145Ile	synonymous	Exon 27 of 29	Prot: NP_000918.2

ABCB1 NM_001348946.2

MANE Select

HGVSc / HGVSpc.3435T>Cp.Ile1145Ile

Exon rankExon 26 of 28

synonymous

Prot: NP_001335875.1UniProt: A4D1D2P08183-1

ABCB1 NM_001348945.2

HGVSc / HGVSpc.3645T>Cp.Ile1215Ile

Exon rankExon 30 of 32

synonymous

Prot: NP_001335874.1

ABCB1 NM_000927.5

HGVSc / HGVSpc.3435T>Cp.Ile1145Ile

Exon rankExon 27 of 29

synonymous

Prot: NP_000918.2

Ensembl Transcripts

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

ABCB1 ENST00000622132.5

TSL:1MANE Select

HGVSc / HGVSpc.3435T>Cp.Ile1145Ile

Exon rankExon 26 of 28

synonymous

Prot: ENSP00000478255.1UniProt: P08183-1

ABCB1 ENST00000265724.8

TSL:1

HGVSc / HGVSpc.3435T>Cp.Ile1145Ile

Exon rankExon 27 of 29

synonymous

Prot: ENSP00000265724.3UniProt: P08183-1

ABCB1 ENST00000488737.6

TSL:1

HGVSc / HGVSpn.1077T>C

Exon rankExon 7 of 9

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.572	AC:86843	Hom:26611	AN:151852	Cov:31
GnomAD2 exomes	AF: 0.504	AC:126736	Hom:	AN:251312	Cov:
GnomAD4 exome	AF: 0.475	AC:694396	Hom:169342	AN:1461786	Cov:61
GnomAD4 genome	AF: 0.572	AC:86962	Hom:26668	AN:151970	Cov:31
TOPMed (Bravo)	AF: 0.599	AC:158578	Hom:50116	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.507	AC:254296	Hom:66917	AN:501144	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.585	AC:1370	Hom:410	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.613	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.447	AC:134	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.577	AC:7500	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.516	AC:1794	Hom:	AN:3476	Cov:
Korea4K (4,157 Koreans)	AF: 0.626	AC:4527	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.571	AC:1147	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.577	AC:70804	Hom:20462	AN:122784	Cov:
Turkish Variome	AF: 0.513	AC:3446	Hom:880	AN:6722	Cov:
UK10K	AF: 0.464	AC:3510	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.625	AC:5599	Hom:1778	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.439 *	4878	11112	0.430 *	7571	17612
BipEx(Bipolar disorder (including schizoaffective))	0.453	12862	28420	0.451	13010	28844
Epi25(Epilepsy)	0.514	21546	41958	0.512	34280	66888
SCHEMA(Schizophrenia)	0.561	87858	156742	0.554	143599	259250

Showing 4 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCB1-related disorder (1)
-	-	1	MDR1 POLYMORPHISM (1)
-	-	-	Tramadol response (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0087
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.022
DANN	Benign	0.56
GPN-Star LLR	N/A	3.7
GPN-Star score	N/A	-0.57
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	-2.5

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1045642;

hg19: chr7-87138645;

COSMIC: COSV55952233;

COSMIC: COSV55952233;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar