7-87585532-A-T

Variant names:

• chr7-87585532-A-T
• rs35810889
• NM_001348946.2:c.266T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001348946.2(ABCB1):​c.266T>A​(p.Met89Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. M89I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0666295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.266T>A	p.Met89Lys	missense_variant	Exon 4 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.476T>A	p.Met159Lys	missense_variant	Exon 8 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.266T>A	p.Met89Lys	missense_variant	Exon 5 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.266T>A	p.Met89Lys	missense_variant	Exon 6 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.266T>A	p.Met89Lys	missense_variant	Exon 4 of 28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.266T>A	p.Met89Lys	missense_variant	Exon 5 of 29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.266T>A	p.Met89Lys	missense_variant	Exon 5 of 28	5		ENSP00000444095.1
ABCB1	ENST00000416177.1	c.*122T>A		downstream_gene_variant		5		ENSP00000399419.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.0020
DANN	Benign	0.52
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.18	T;.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L;L;L
PhyloP100		-1.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.51	.;N;N
REVEL	Benign	0.17
Sift	Benign	0.90	.;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.10
MutPred		0.56		Gain of ubiquitination at M89 (P = 0.0104);Gain of ubiquitination at M89 (P = 0.0104);Gain of ubiquitination at M89 (P = 0.0104);
MVP		0.14
MPC		0.32
ClinPred		0.062	T
GERP RS		-3.0
Varity_R		0.41
gMVP		0.45
Mutation Taster		=93/7	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: rs35810889; hg19: chr7-87214848;