chr3-183978614-A-G

Variant names:

• chr3-183978614-A-G
• rs1132776
• NM_005688.4:c.1185T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005688.4(ABCC5):​c.1185T>C​(p.Ala395Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,613,508 control chromosomes in the GnomAD database, including 264,225 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (29078 hom., cov: 32)
  • Exomes 𝑓: 0.56 (235147 hom.)
• Consequence: ABCC5 NM_005688.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91
• Publications: 45 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC5	NM_005688.4	c.1185T>C	p.Ala395Ala	synonymous_variant	Exon 9 of 30	ENST00000334444.11	NP_005679.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC5	ENST00000334444.11	c.1185T>C	p.Ala395Ala	synonymous_variant	Exon 9 of 30	1	NM_005688.4	ENSP00000333926.6
ABCC5	ENST00000265586.10	c.1185T>C	p.Ala395Ala	synonymous_variant	Exon 9 of 29	5		ENSP00000265586.6
ABCC5	ENST00000437205.5	n.1185T>C		non_coding_transcript_exon_variant	Exon 9 of 30	5		ENSP00000403510.1
ABCC5	ENST00000492216.1	n.736T>C		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92855 AN: 151868 Hom.: 29048 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.624

GnomAD2 exomes AF: 0.578 AC: 144055 AN: 249052 AF XY: 0.573

Gnomad AFR exome AF: 0.740

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.851

Gnomad FIN exome AF: 0.502

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.564 AC: 824033 AN: 1461522 Hom.: 235147 Cov.: 51 AF XY: 0.563 AC XY: 409141 AN XY: 727082

African (AFR) AF: 0.733 AC: 24518 AN: 33458

American (AMR) AF: 0.528 AC: 23575 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 14430 AN: 26132

East Asian (EAS) AF: 0.853 AC: 33851 AN: 39698

South Asian (SAS) AF: 0.541 AC: 46629 AN: 86228

European-Finnish (FIN) AF: 0.510 AC: 27203 AN: 53380

Middle Eastern (MID) AF: 0.583 AC: 3362 AN: 5764

European-Non Finnish (NFE) AF: 0.554 AC: 615822 AN: 1111852

Other (OTH) AF: 0.574 AC: 34643 AN: 60378

GnomAD4 genome AF: 0.611 AC: 92935 AN: 151986 Hom.: 29078 Cov.: 32 AF XY: 0.606 AC XY: 45023 AN XY: 74300

African (AFR) AF: 0.725 AC: 30047 AN: 41448

American (AMR) AF: 0.578 AC: 8819 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1913 AN: 3472

East Asian (EAS) AF: 0.853 AC: 4403 AN: 5164

South Asian (SAS) AF: 0.553 AC: 2661 AN: 4812

European-Finnish (FIN) AF: 0.500 AC: 5277 AN: 10552

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37900 AN: 67956

Other (OTH) AF: 0.626 AC: 1323 AN: 2112

Alfa AF: 0.577 Hom.: 114355

Bravo AF: 0.622

Asia WGS AF: 0.707 AC: 2459 AN: 3478

EpiCase AF: 0.564

EpiControl AF: 0.577

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.49
PhyloP100		-1.9
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1132776; hg19: chr3-183696402; COSMIC: COSV55586679;