dbSNP rs4148437: ABCC4:c.186-5T>C (chr13-95247100-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005845.5(ABCC4):c.186-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,607,292 control chromosomes in the GnomAD database, including 98,841 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 7182 hom., cov: 32)

Exomes 𝑓: 0.35 ( 91659 hom. )

Consequence

ABCC4
NM_005845.5 splice_region, intron

Scores

Splicing: ADA: 0.0003013

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.252

Publications

19 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:

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 (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5 link	c.186-5T>C		splice_region_variant, intron_variant	Intron 2 of 30	ENST00000645237.2	NP_005836.2	O15439-1A8K2Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2 link	c.186-5T>C		splice_region_variant, intron_variant	Intron 2 of 30		NM_005845.5	ENSP00000494609.1		O15439-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42274

AN:

151992

Hom.:

7180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0871

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.315

AC:

77384

AN:

245454

AF XY:

0.317

show subpopulations

Gnomad AFR exome

AF:

0.0803

Gnomad AMR exome

AF:

0.334

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.415

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.325

GnomAD4 exome

AF:

0.347

AC:

505008

AN:

1455182

Hom.:

91659

Cov.:

AF XY:

0.344

AC XY:

249303

AN XY:

723854

show subpopulations

African (AFR)

AF:

0.0746

AC:

2460

AN:

32954

American (AMR)

AF:

0.337

AC:

14506

AN:

43096

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

8020

AN:

25868

East Asian (EAS)

AF:

0.140

AC:

5558

AN:

39670

South Asian (SAS)

AF:

0.232

AC:

19689

AN:

84686

European-Finnish (FIN)

AF:

0.407

AC:

21692

AN:

53300

Middle Eastern (MID)

AF:

0.254

AC:

1454

AN:

5728

European-Non Finnish (NFE)

AF:

0.371

AC:

412103

AN:

1109780

Other (OTH)

AF:

0.325

AC:

19526

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15509

31018

46528

62037

77546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12774

25548

38322

51096

63870

<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:

0.278

AC:

42269

AN:

152110

Hom.:

7182

Cov.:

AF XY:

0.281

AC XY:

20878

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0869

AC:

3607

AN:

41524

American (AMR)

AF:

0.329

AC:

5033

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1098

AN:

3472

East Asian (EAS)

AF:

0.178

AC:

921

AN:

5180

South Asian (SAS)

AF:

0.233

AC:

1121

AN:

4818

European-Finnish (FIN)

AF:

0.421

AC:

4444

AN:

10558

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.366

AC:

24882

AN:

67962

Other (OTH)

AF:

0.309

AC:

653

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1464

2928

4392

5856

7320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<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:

0.338

Hom.:

18478

Bravo

AF:

0.267

Asia WGS

AF:

0.207

AC:

721

AN:

3478

EpiCase

AF:

0.363

EpiControl

AF:

0.360

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.4

(source)

DANN

Benign

0.70

PhyloP100

0.25

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.022

SpliceAI score (max)

0.13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over