rs1045642

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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 was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1145I) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Consequence

ABCB1
NM_001348946.2 missense

Scores

3
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.52
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCB1NM_001348946.2 linkuse as main transcriptc.3435T>G p.Ile1145Met missense_variant 26/28 ENST00000622132.5 NP_001335875.1
ABCB1NM_001348945.2 linkuse as main transcriptc.3645T>G p.Ile1215Met missense_variant 30/32 NP_001335874.1
ABCB1NM_000927.5 linkuse as main transcriptc.3435T>G p.Ile1145Met missense_variant 27/29 NP_000918.2
ABCB1NM_001348944.2 linkuse as main transcriptc.3435T>G p.Ile1145Met missense_variant 28/30 NP_001335873.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCB1ENST00000622132.5 linkuse as main transcriptc.3435T>G p.Ile1145Met missense_variant 26/281 NM_001348946.2 ENSP00000478255 P1P08183-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
61
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Benign
1.9
L;L;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.8
.;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0010
.;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
0.82
P;P;.
Vest4
0.66
MutPred
0.65
Gain of disorder (P = 0.0486);Gain of disorder (P = 0.0486);.;
MVP
0.68
MPC
0.81
ClinPred
0.98
D
GERP RS
-6.8
Varity_R
0.72
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1045642; hg19: chr7-87138645; API