rs1045642

Variant names:

• chr7-87509329-A-C
• rs1045642
• NM_001348946.2:c.3435T>G
• ABCB1 p.Ile1145Met

Your query was ambiguous. Multiple possible variants found:

• chr7-87509329-A-C
• chr7-87509329-A-G
• chr7-87509329-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001348946.2(ABCB1):c.3435T>G (p.Ile1145Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I1145= (synonymous): Benign (ClinVar VariationId 225939, 2 stars)

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52
• Publications: 3153 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

Our verdict: Uncertain_significance. The variant received 2 points.

• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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>G	p.Ile1145Met	missense	Exon 26 of 28	NP_001335875.1	A4D1D2
	ABCB1	NM_001348945.2		c.3645T>G	p.Ile1215Met	missense	Exon 30 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.3435T>G	p.Ile1145Met	missense	Exon 27 of 29	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.3435T>G	p.Ile1145Met	missense	Exon 26 of 28	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.3435T>G	p.Ile1145Met	missense	Exon 27 of 29	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000488737.6	TSL:1	n.1077T>G		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	0.13
DANN	Uncertain	0.99
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.9	L
PhyloP100		-2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.72
popEVE	Benign	-3.5
VESM-3B	Benign	-8.5
FuncVEP CTI	Pathogenic	0.54
AlphaGenome AVI	Benign	0.47
GPN-Star LLR		-4.1
GPN-Star score		4.1
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2
Pangolin (max)	Benign	0.050

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.

Other links and lift over

dbSNP: rs1045642;

hg19: chr7-87138645;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar