rs2032586

chr7-87550300-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001348946.2(ABCB1):c.1225-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,614,124 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: ABCB1 NM_001348946.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001700
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-87550300-C-T is Benign according to our data. Variant chr7-87550300-C-T is described in ClinVar as [Benign]. Clinvar id is 729681.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 528 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.1225-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000622132.5
ABCB1	NM_000927.5	c.1225-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ABCB1	NM_001348944.2	c.1225-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ABCB1	NM_001348945.2	c.1435-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.1225-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.1225-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
ABCB1	ENST00000543898.5	c.1033-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152162 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000835 AC: 210 AN: 251366 Hom.: 1 AF XY: 0.000714 AC XY: 97 AN XY: 135856

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461844 Hom.: 8 Cov.: 35 AF XY: 0.000366 AC XY: 266 AN XY: 727228

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00350 AC: 533 AN: 152280 Hom.: 3 Cov.: 33 AF XY: 0.00325 AC XY: 242 AN XY: 74472

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.00368

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs2032586; hg19: chr7-87179616;