13-95210754-C-A

Variant names:

• chr13-95210754-C-A
• rs11568658
• NM_005845.5:c.559G>T

Variant summary

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

The NM_005845.5(ABCC4):​c.559G>T​(p.Gly187Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0308 in 1,613,498 control chromosomes in the GnomAD database, including 1,431 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 0.032 (161 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1270 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 69 publications found

Genes affected

ABCC4 (HGNC:55): (ATP binding cassette subfamily C member 4 (PEL blood group)) 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 family member plays a role in cellular detoxification as a pump for its substrate, organic anions. It may also function in prostaglandin-mediated cAMP signaling in ciliogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ABCC4 Gene-Disease associations (from GenCC):

• qualitative platelet defect

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052810013).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005845.5. 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
	ABCC4	NM_005845.5	MANE Select	c.559G>T	p.Gly187Trp	missense	Exon 5 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.559G>T	p.Gly187Trp	missense	Exon 5 of 30	NP_001288758.1
	ABCC4	NM_001105515.3		c.559G>T	p.Gly187Trp	missense	Exon 5 of 21	NP_001098985.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.559G>T	p.Gly187Trp	missense	Exon 5 of 31	ENSP00000494609.1
	ABCC4	ENST00000629385.1	TSL:1	c.559G>T	p.Gly187Trp	missense	Exon 5 of 21	ENSP00000487081.1
	ABCC4	ENST00000646439.1		c.559G>T	p.Gly187Trp	missense	Exon 5 of 30	ENSP00000494751.1

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4849 AN: 152130 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0576

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0490 AC: 12291 AN: 251012 AF XY: 0.0474

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0433

GnomAD4 exome AF: 0.0307 AC: 44919 AN: 1461250 Hom.: 1270 Cov.: 31 AF XY: 0.0316 AC XY: 22972 AN XY: 726946

African (AFR) AF: 0.00397 AC: 133 AN: 33472

American (AMR) AF: 0.114 AC: 5063 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 1044 AN: 26114

East Asian (EAS) AF: 0.125 AC: 4955 AN: 39660

South Asian (SAS) AF: 0.0612 AC: 5273 AN: 86132

European-Finnish (FIN) AF: 0.0381 AC: 2034 AN: 53404

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5764

European-Non Finnish (NFE) AF: 0.0219 AC: 24330 AN: 1111758

Other (OTH) AF: 0.0311 AC: 1875 AN: 60372

GnomAD4 genome AF: 0.0318 AC: 4846 AN: 152248 Hom.: 161 Cov.: 32 AF XY: 0.0355 AC XY: 2643 AN XY: 74430

African (AFR) AF: 0.00477 AC: 198 AN: 41552

American (AMR) AF: 0.0871 AC: 1332 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3470

East Asian (EAS) AF: 0.114 AC: 591 AN: 5164

South Asian (SAS) AF: 0.0579 AC: 279 AN: 4820

European-Finnish (FIN) AF: 0.0457 AC: 484 AN: 10600

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1596 AN: 68022

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0279 Hom.: 478

Bravo AF: 0.0356

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0447 AC: 5430

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.0263

EpiControl AF: 0.0277

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		3.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.85
ClinPred		0.086	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.69
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs11568658; hg19: chr13-95863008; COSMIC: COSV65310023;