NM_005845.5:c.52C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005845.5(ABCC4):c.52C>A(p.Leu18Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,595,572 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 20 hom., cov: 33)

Exomes 𝑓: 0.017 ( 285 hom. )

Consequence

ABCC4
NM_005845.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.112

Publications

16 publications found

Variant links:

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

ABCC4 links:

ENSG00000297451 (HGNC:):

ENSG00000297451 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0037238002).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2338/152174) while in subpopulation SAS AF = 0.0223 (108/4834). AF 95% confidence interval is 0.0189. There are 20 homozygotes in GnomAd4. There are 1108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCC4	NM_005845.5	MANE Select	c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	NP_005836.2
ABCC4	NM_001301829.2		c.52C>A	p.Leu18Ile	missense	Exon 1 of 30	NP_001288758.1
ABCC4	NM_001105515.3		c.52C>A	p.Leu18Ile	missense	Exon 1 of 21	NP_001098985.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCC4	ENST00000645237.2	MANE Select	c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	ENSP00000494609.1
ABCC4	ENST00000629385.1	TSL:1	c.52C>A	p.Leu18Ile	missense	Exon 1 of 21	ENSP00000487081.1
ABCC4	ENST00000967420.1		c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	ENSP00000637479.1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2341

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00881

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0490

Gnomad EAS

AF:

0.0212

Gnomad SAS

AF:

0.0227

Gnomad FIN

AF:

0.00388

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0167

AC:

3832

AN:

228908

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0491

Gnomad EAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.00474

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0170

AC:

24536

AN:

1443398

Hom.:

285

Cov.:

AF XY:

0.0173

AC XY:

12440

AN XY:

717912

show subpopulations

African (AFR)

AF:

0.0130

AC:

410

AN:

31542

American (AMR)

AF:

0.0124

AC:

530

AN:

42854

Ashkenazi Jewish (ASJ)

AF:

0.0480

AC:

1230

AN:

25614

East Asian (EAS)

AF:

0.0178

AC:

678

AN:

38138

South Asian (SAS)

AF:

0.0216

AC:

1807

AN:

83778

European-Finnish (FIN)

AF:

0.00460

AC:

241

AN:

52436

Middle Eastern (MID)

AF:

0.0287

AC:

164

AN:

5714

European-Non Finnish (NFE)

AF:

0.0165

AC:

18198

AN:

1103698

Other (OTH)

AF:

0.0214

AC:

1278

AN:

59624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1154

2307

3461

4614

5768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

738

1476

2214

2952

3690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2338

AN:

152174

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1108

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0141

AC:

586

AN:

41560

American (AMR)

AF:

0.0146

AC:

223

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0490

AC:

170

AN:

3470

East Asian (EAS)

AF:

0.0213

AC:

110

AN:

5172

South Asian (SAS)

AF:

0.0223

AC:

108

AN:

4834

European-Finnish (FIN)

AF:

0.00388

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0152

AC:

1032

AN:

67970

Other (OTH)

AF:

0.0237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

118

236

355

473

591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0164

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0169

AC:

2035

Asia WGS

AF:

0.0260

AC:

AN:

3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.046

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.37

PhyloP100

0.11

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.13

REVEL

Benign

0.030

Sift

Benign

0.39

Sift4G

Benign

0.57

Polyphen

0.30

Vest4

0.036

MPC

0.26

ClinPred

0.0078

GERP RS

2.8

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.24

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over