chr7-87504335-C-A

Variant names:

• chr7-87504335-C-A
• NM_001348946.2:c.3751G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001348946.2(ABCB1):​c.3751G>T​(p.Val1251Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1251I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.3751G>T	p.Val1251Phe	missense_variant	Exon 28 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.3961G>T	p.Val1321Phe	missense_variant	Exon 32 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.3751G>T	p.Val1251Phe	missense_variant	Exon 29 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.3751G>T	p.Val1251Phe	missense_variant	Exon 30 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.3751G>T	p.Val1251Phe	missense_variant	Exon 28 of 28	1	NM_001348946.2	ENSP00000478255.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.92	P;P;.
Vest4		0.51
MutPred		0.56		Gain of catalytic residue at V1251 (P = 0.0227);Gain of catalytic residue at V1251 (P = 0.0227);.;
MVP		0.50
MPC		0.71
ClinPred		1.0	D
GERP RS		-3.2
Varity_R		0.69
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-87133651;