rs1045642

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 Likely benign.

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

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]

ACMG classification

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	UniProt
ABCB1	NM_001348946.2	c.3435T>G	p.Ile1145Met	missense_variant	26/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.3645T>G	p.Ile1215Met	missense_variant	30/32
ABCB1	NM_000927.5	c.3435T>G	p.Ile1145Met	missense_variant	27/29
ABCB1	NM_001348944.2	c.3435T>G	p.Ile1145Met	missense_variant	28/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.3435T>G	p.Ile1145Met	missense_variant	26/28	1	NM_001348946.2	P1

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

Other links and lift over

dbSNP: rs1045642; hg19: chr7-87138645;