NM_001348946.2:c.3435T>A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP7

The NM_001348946.2(ABCB1):c.3435T>A (p.Ile1145Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCB1 NM_001348946.2 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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).
	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).

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>A p.Ile1145Ile	synonymous	Exon 26 of 28	Prot: NP_001335875.1 UniProt:
	ABCB1 NM_001348945.2		c.3645T>A p.Ile1215Ile	synonymous	Exon 30 of 32	Prot: NP_001335874.1
	ABCB1 NM_000927.5		c.3435T>A p.Ile1145Ile	synonymous	Exon 27 of 29	Prot: NP_000918.2

ABCB1 NM_001348946.2

MANE Select

HGVSc / HGVSpc.3435T>Ap.Ile1145Ile

Exon rankExon 26 of 28

synonymous

Prot: NP_001335875.1UniProt: A4D1D2P08183-1

ABCB1 NM_001348945.2

HGVSc / HGVSpc.3645T>Ap.Ile1215Ile

Exon rankExon 30 of 32

synonymous

Prot: NP_001335874.1

ABCB1 NM_000927.5

HGVSc / HGVSpc.3435T>Ap.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>A p.Ile1145Ile	synonymous	Exon 26 of 28	Prot: ENSP00000478255.1 UniProt:
	ABCB1 ENST00000265724.8	TSL:1	c.3435T>A p.Ile1145Ile	synonymous	Exon 27 of 29	Prot: ENSP00000265724.3 UniProt:
	ABCB1 ENST00000488737.6	TSL:1	n.1077T>A	non_coding_transcript_exon	Exon 7 of 9	Prot:

ABCB1 ENST00000622132.5

TSL:1MANE Select

HGVSc / HGVSpc.3435T>Ap.Ile1145Ile

Exon rankExon 26 of 28

synonymous

Prot: ENSP00000478255.1UniProt: P08183-1

ABCB1 ENST00000265724.8

TSL:1

HGVSc / HGVSpc.3435T>Ap.Ile1145Ile

Exon rankExon 27 of 29

synonymous

Prot: ENSP00000265724.3UniProt: P08183-1

ABCB1 ENST00000488737.6

TSL:1

HGVSc / HGVSpn.1077T>A

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:61
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0090
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.021
DANN	Benign	0.55
GPN-Star LLR	N/A	-0.53
GPN-Star score	N/A	0.53
PhyloP100	Benign	-2.5

Showing 7 of 7 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar