7-87509343-A-T

Position:

• chr7-87509343-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001348946.2(ABCB1):​c.3421T>A​(p.Ser1141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,076 control chromosomes in the GnomAD database, including 155 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 Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (83 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.131

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=0.0023221076).
• BP6: Variant 7-87509343-A-T is Benign according to our data. Variant chr7-87509343-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038471.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.3421T>A	p.Ser1141Thr	missense_variant	26/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.3631T>A	p.Ser1211Thr	missense_variant	30/32
ABCB1	NM_000927.5	c.3421T>A	p.Ser1141Thr	missense_variant	27/29
ABCB1	NM_001348944.2	c.3421T>A	p.Ser1141Thr	missense_variant	28/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.3421T>A	p.Ser1141Thr	missense_variant	26/28	1	NM_001348946.2	P1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2738 AN: 152122 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00468 AC: 1176 AN: 251304 Hom.: 34 AF XY: 0.00341 AC XY: 463 AN XY: 135810

Gnomad AFR exome AF: 0.0648

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00178 AC: 2602 AN: 1461836 Hom.: 83 Cov.: 35 AF XY: 0.00149 AC XY: 1084 AN XY: 727216

Gnomad4 AFR exome AF: 0.0643

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0181 AC: 2754 AN: 152240 Hom.: 72 Cov.: 32 AF XY: 0.0169 AC XY: 1259 AN XY: 74452

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00269 Hom.: 6

Bravo AF: 0.0205

ESP6500AA AF: 0.0615 AC: 271

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00615 AC: 747

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ABCB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.84
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T;.;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.37	N;N;.
MutationTaster	Benign	0.71	D;D
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.090
MVP		0.61
MPC		0.19
ClinPred		0.0096	T
GERP RS		3.6
Varity_R		0.13
gMVP		0.66

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: rs2229107; hg19: chr7-87138659;