rs28364274

chr7-87504335-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001348946.2(ABCB1):c.3751G>A(p.Val1251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,050 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0048 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0130

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020558536).
• BP6: Variant 7-87504335-C-T is Benign according to our data. Variant chr7-87504335-C-T is described in ClinVar as [Benign]. Clinvar id is 778935.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00476 (725/152348) while in subpopulation AMR AF= 0.0444 (680/15304). AF 95% confidence interval is 0.0417. There are 32 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 722 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.3751G>A	p.Val1251Ile	missense_variant	28/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.3961G>A	p.Val1321Ile	missense_variant	32/32
ABCB1	NM_000927.5	c.3751G>A	p.Val1251Ile	missense_variant	29/29
ABCB1	NM_001348944.2	c.3751G>A	p.Val1251Ile	missense_variant	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.3751G>A	p.Val1251Ile	missense_variant	28/28	1	NM_001348946.2	P1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152230 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00468 AC: 1177 AN: 251374 Hom.: 22 AF XY: 0.00365 AC XY: 496 AN XY: 135860

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00130 AC: 1903 AN: 1461702 Hom.: 36 Cov.: 31 AF XY: 0.00117 AC XY: 853 AN XY: 727146

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00902

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00476 AC: 725 AN: 152348 Hom.: 32 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74498

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00101 Hom.: 4

Bravo AF: 0.00601

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00304 AC: 369

Asia WGS AF: 0.00231 AC: 8 AN: 3476

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 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.4
Dann	Benign	0.71
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;.;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.067
MVP		0.14
MPC		0.17
ClinPred		0.0021	T
GERP RS		-3.2
Varity_R		0.046
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs28364274; hg19: chr7-87133651; COSMIC: COSV55952437; COSMIC: COSV55952437;