7-87550300-C-T

Variant names:

• chr7-87550300-C-T
• rs2032586
• NM_001348946.2:c.1225-4G>A

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00001700
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46
• Publications: 6 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: Benign. The variant received -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 VariationId is 729681.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 533 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348946.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.1225-4G>A		splice_region intron	N/A	NP_001335875.1
	ABCB1	NM_001348945.2		c.1435-4G>A		splice_region intron	N/A	NP_001335874.1
	ABCB1	NM_000927.5		c.1225-4G>A		splice_region intron	N/A	NP_000918.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.1225-4G>A		splice_region intron	N/A	ENSP00000478255.1
	ABCB1	ENST00000265724.8	TSL:1	c.1225-4G>A		splice_region intron	N/A	ENSP00000265724.3
	ABCB1	ENST00000543898.5	TSL:5	c.1033-4G>A		splice_region intron	N/A	ENSP00000444095.1

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

GnomAD2 exomes AF: 0.000835 AC: 210 AN: 251366 AF XY: 0.000714

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 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

African (AFR) AF: 0.0137 AC: 459 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5758

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112002

Other (OTH) AF: 0.00114 AC: 69 AN: 60394

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

African (AFR) AF: 0.0124 AC: 515 AN: 41544

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00181 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

Jul 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.42
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2032586; hg19: chr7-87179616;