NM_001348946.2:c.3421T>C

Variant names:

• chr7-87509343-A-G
• rs2229107
• NM_001348946.2:c.3421T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001348946.2(ABCB1):​c.3421T>C​(p.Ser1141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. S1141T) 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: 0.131
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41457894).

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.3421T>C	p.Ser1141Pro	missense	Exon 26 of 28	NP_001335875.1
	ABCB1	NM_001348945.2		c.3631T>C	p.Ser1211Pro	missense	Exon 30 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.3421T>C	p.Ser1141Pro	missense	Exon 27 of 29	NP_000918.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.3421T>C	p.Ser1141Pro	missense	Exon 26 of 28	ENSP00000478255.1
	ABCB1	ENST00000265724.8	TSL:1	c.3421T>C	p.Ser1141Pro	missense	Exon 27 of 29	ENSP00000265724.3
	ABCB1	ENST00000488737.6	TSL:1	n.1063T>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.13
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.45	T
Sift4G	Benign	0.33	T
Polyphen		0.013	B
Vest4		0.20
MutPred		0.58		Loss of phosphorylation at S1141 (P = 0.0309)
MVP		0.45
MPC		0.27
ClinPred		0.15	T
GERP RS		3.6
Varity_R		0.50
gMVP		0.82
Mutation Taster		=73/27	polymorphism

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: rs2229107; hg19: chr7-87138659;