7-87509329-A-G

Variant names:

• chr7-87509329-A-G
• rs1045642
• NM_001348946.2:c.3435T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001348946.2(ABCB1):​c.3435T>C​(p.Ile1145Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,756 control chromosomes in the GnomAD database, including 196,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26668 hom., cov: 31)
  • Exomes 𝑓: 0.48 (169342 hom.)
• Consequence: ABCB1 NM_001348946.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.52
• Publications: 3092 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-87509329-A-G is Benign according to our data. Variant chr7-87509329-A-G is described in ClinVar as Benign. ClinVar VariationId is 225939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.3435T>C	p.Ile1145Ile	synonymous	Exon 26 of 28	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.3645T>C	p.Ile1215Ile	synonymous	Exon 30 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.3435T>C	p.Ile1145Ile	synonymous	Exon 27 of 29	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.3435T>C	p.Ile1145Ile	synonymous	Exon 26 of 28	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.3435T>C	p.Ile1145Ile	synonymous	Exon 27 of 29	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000488737.6	TSL:1	n.1077T>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86843 AN: 151852 Hom.: 26611 Cov.: 31

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.504 AC: 126736 AN: 251312 AF XY: 0.491

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.632

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.475 AC: 694396 AN: 1461786 Hom.: 169342 Cov.: 61 AF XY: 0.472 AC XY: 342927 AN XY: 727204

African (AFR) AF: 0.821 AC: 27480 AN: 33480

American (AMR) AF: 0.547 AC: 24460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16937 AN: 26134

East Asian (EAS) AF: 0.603 AC: 23932 AN: 39694

South Asian (SAS) AF: 0.396 AC: 34151 AN: 86252

European-Finnish (FIN) AF: 0.390 AC: 20825 AN: 53408

Middle Eastern (MID) AF: 0.551 AC: 3174 AN: 5764

European-Non Finnish (NFE) AF: 0.461 AC: 512604 AN: 1111936

Other (OTH) AF: 0.511 AC: 30833 AN: 60394

GnomAD4 genome AF: 0.572 AC: 86962 AN: 151970 Hom.: 26668 Cov.: 31 AF XY: 0.569 AC XY: 42247 AN XY: 74274

African (AFR) AF: 0.797 AC: 33035 AN: 41442

American (AMR) AF: 0.569 AC: 8684 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2264 AN: 3466

East Asian (EAS) AF: 0.619 AC: 3196 AN: 5164

South Asian (SAS) AF: 0.413 AC: 1988 AN: 4818

European-Finnish (FIN) AF: 0.379 AC: 3998 AN: 10554

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31853 AN: 67940

Other (OTH) AF: 0.600 AC: 1265 AN: 2108

Alfa AF: 0.502 Hom.: 61881

Bravo AF: 0.599

Asia WGS AF: 0.516 AC: 1794 AN: 3476

EpiCase AF: 0.478

EpiControl AF: 0.477

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCB1-related disorder (1)
-	-	1	MDR1 POLYMORPHISM (1)
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.022
DANN	Benign	0.56
PhyloP100		-2.5
Mutation Taster		=99/1	polymorphism (auto)

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: rs1045642; hg19: chr7-87138645; COSMIC: COSV55952233; COSMIC: COSV55952233;