rs36008564

Variant names:

• chr7-87561309-T-A
• rs36008564
• NM_001348946.2:c.781A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-87561309-T-A
• chr7-87561309-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001348946.2(ABCB1):​c.781A>T​(p.Ile261Phe) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I261V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.898
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.781A>T	p.Ile261Phe	missense_variant	Exon 8 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.991A>T	p.Ile331Phe	missense_variant	Exon 12 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.781A>T	p.Ile261Phe	missense_variant	Exon 9 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.781A>T	p.Ile261Phe	missense_variant	Exon 10 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.781A>T	p.Ile261Phe	missense_variant	Exon 8 of 28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.781A>T	p.Ile261Phe	missense_variant	Exon 9 of 29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.589A>T	p.Ile197Phe	missense_variant	Exon 8 of 28	5		ENSP00000444095.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.3	H;H;.
PhyloP100		0.90
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	.;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.026	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.63		Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);.;
MVP		0.88
MPC		0.68
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.74
gMVP		0.95
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36008564; hg19: chr7-87190625;