chr3-183949982-T-A

Position:

• chr3-183949982-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005688.4(ABCC5):​c.3088A>T​(p.Ile1030Phe) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC5 NM_005688.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0590

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ABCC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.18105668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC5	NM_005688.4	c.3088A>T	p.Ile1030Phe	missense_variant	21/30	ENST00000334444.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC5	ENST00000334444.11	c.3088A>T	p.Ile1030Phe	missense_variant	21/30	1	NM_005688.4	P1
ABCC5	ENST00000265586.10	c.3088A>T	p.Ile1030Phe	missense_variant	21/29	5
ABCC5	ENST00000437205.5	c.*1781A>T		3_prime_UTR_variant, NMD_transcript_variant	21/30	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.3088A>T (p.I1030F) alteration is located in exon 21 (coding exon 20) of the ABCC5 gene. This alteration results from a A to T substitution at nucleotide position 3088, causing the isoleucine (I) at amino acid position 1030 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.51	N;N
MutationTaster	Benign	0.73	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.27
Sift	Benign	0.70	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0010	B;.
Vest4		0.33
MutPred		0.54		Gain of methylation at R1033 (P = 0.0679);Gain of methylation at R1033 (P = 0.0679);
MVP		0.49
MPC		0.81
ClinPred		0.26	T
GERP RS		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs781403637; hg19: chr3-183667770;