3-183919934-T-G

Variant names:

• chr3-183919934-T-G
• rs3805114
• NM_005688.4:c.*1366A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005688.4(ABCC5):​c.*1366A>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 152,626 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (487 hom., cov: 33)
  • Exomes 𝑓: 0.064 (4 hom.)
• Consequence: ABCC5 NM_005688.4 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.411
• Publications: 10 publications found

Genes affected

ABCC5 (HGNC:56): (ATP binding cassette subfamily C member 5) The 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 MRP subfamily which is involved in multi-drug resistance. This protein functions in the cellular export of its substrate, cyclic nucleotides. This export contributes to the degradation of phosphodiesterases and possibly an elimination pathway for cyclic nucleotides. Studies show that this protein provides resistance to thiopurine anticancer drugs, 6-mercatopurine and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine. This protein may be involved in resistance to thiopurines in acute lymphoblastic leukemia and antiretroviral nucleoside analogs in HIV-infected patients. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC5	NM_005688.4	c.*1366A>C		splice_region_variant	Exon 30 of 30	ENST00000334444.11	NP_005679.2
ABCC5	NM_005688.4	c.*1366A>C		3_prime_UTR_variant	Exon 30 of 30	ENST00000334444.11	NP_005679.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC5	ENST00000334444.11	c.*1366A>C		splice_region_variant	Exon 30 of 30	1	NM_005688.4	ENSP00000333926.6
ABCC5	ENST00000334444.11	c.*1366A>C		3_prime_UTR_variant	Exon 30 of 30	1	NM_005688.4	ENSP00000333926.6
ABCC5	ENST00000265586.10	c.*1366A>C		downstream_gene_variant		5		ENSP00000265586.6
ABCC5	ENST00000437205.5	n.*4373A>C		downstream_gene_variant		5		ENSP00000403510.1

Frequencies

GnomAD3 genomes AF: 0.0765 AC: 11646 AN: 152148 Hom.: 485 Cov.: 33

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.0723

GnomAD4 exome AF: 0.0642 AC: 23 AN: 358 Hom.: 4 Cov.: 0 AF XY: 0.0519 AC XY: 11 AN XY: 212

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0629 AC: 22 AN: 350

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.0765 AC: 11655 AN: 152268 Hom.: 487 Cov.: 33 AF XY: 0.0764 AC XY: 5687 AN XY: 74454

African (AFR) AF: 0.0803 AC: 3335 AN: 41534

American (AMR) AF: 0.0516 AC: 790 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3472

East Asian (EAS) AF: 0.172 AC: 892 AN: 5172

South Asian (SAS) AF: 0.118 AC: 568 AN: 4826

European-Finnish (FIN) AF: 0.0708 AC: 752 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4731 AN: 68032

Other (OTH) AF: 0.0716 AC: 151 AN: 2110

Alfa AF: 0.0749 Hom.: 1997

Bravo AF: 0.0736

Asia WGS AF: 0.129 AC: 450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		0.41
Mutation Taster		=100/0	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: rs3805114; hg19: chr3-183637722;