rs553921855

Variant names:

• chr3-183921314-C-T
• rs553921855
• NM_005688.4:c.4300G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005688.4(ABCC5):​c.4300G>A​(p.Ala1434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,582,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: ABCC5 NM_005688.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086687505).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005688.4. 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
	ABCC5	NM_005688.4	MANE Select	c.4300G>A	p.Ala1434Thr	missense	Exon 30 of 30	NP_005679.2	O15440-1
	ABCC5	NM_001320032.2		c.2884G>A	p.Ala962Thr	missense	Exon 30 of 30	NP_001306961.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC5	ENST00000334444.11	TSL:1 MANE Select	c.4300G>A	p.Ala1434Thr	missense	Exon 30 of 30	ENSP00000333926.6	O15440-1
	ABCC5	ENST00000898238.1		c.4300G>A	p.Ala1434Thr	missense	Exon 30 of 30	ENSP00000568297.1
	ABCC5	ENST00000956865.1		c.4300G>A	p.Ala1434Thr	missense	Exon 30 of 30	ENSP00000626924.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000812 AC: 2 AN: 246166 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1429878 Hom.: 0 Cov.: 26 AF XY: 0.00000701 AC XY: 5 AN XY: 713422

African (AFR) AF: 0.00 AC: 0 AN: 32670

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39246

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084444

Other (OTH) AF: 0.00 AC: 0 AN: 59238

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.28
Sift	Uncertain	0.022	D
Sift4G	Benign	0.89	T
Polyphen		0.050	B
Vest4		0.14
MutPred		0.21		Loss of ubiquitination at K1432 (P = 0.0532)
MVP		0.24
MPC		0.49
ClinPred		0.34	T
GERP RS		5.0
Varity_R		0.099
gMVP		0.52
Mutation Taster		=90/10	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: rs553921855; hg19: chr3-183639102; COSMIC: COSV99657448; COSMIC: COSV99657448;