dbSNP rs11568694: ABCC4:p.Val854Phe (chr13-95083266-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005845.5(ABCC4):c.2560G>T(p.Val854Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,613,880 control chromosomes in the GnomAD database, including 108 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 0.0051 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 106 hom. )

Consequence

ABCC4
NM_005845.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

21 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 (MetaRNN=0.006900698).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00511 (778/152212) while in subpopulation SAS AF = 0.0264 (127/4804). AF 95% confidence interval is 0.0227. There are 2 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5 link	c.2560G>T	p.Val854Phe	missense_variant	Exon 21 of 31	ENST00000645237.2	NP_005836.2	O15439-1A8K2Q2
ABCC4	NM_001301829.2 link	c.2419G>T	p.Val807Phe	missense_variant	Exon 20 of 30		NP_001288758.1	O15439-2A8K2Q2
ABCC4	XM_047430034.1 link	c.2431G>T	p.Val811Phe	missense_variant	Exon 21 of 31		XP_047285990.1
ABCC4	XM_047430035.1 link	c.2011G>T	p.Val671Phe	missense_variant	Exon 18 of 28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2 link	c.2560G>T	p.Val854Phe	missense_variant	Exon 21 of 31		NM_005845.5	ENSP00000494609.1		O15439-1

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

777

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0264

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00706

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00758

AC:

1901

AN:

250856

AF XY:

0.00906

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00686

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00808

AC:

11811

AN:

1461668

Hom.:

106

Cov.:

AF XY:

0.00891

AC XY:

6479

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33466

American (AMR)

AF:

0.00322

AC:

144

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00410

AC:

107

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39680

South Asian (SAS)

AF:

0.0303

AC:

2613

AN:

86240

European-Finnish (FIN)

AF:

0.00101

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00903

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00747

AC:

8309

AN:

1111870

Other (OTH)

AF:

0.00835

AC:

504

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

577

1154

1731

2308

2885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.00511

AC:

778

AN:

152212

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41540

American (AMR)

AF:

0.00458

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0264

AC:

127

AN:

4804

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00707

AC:

481

AN:

68014

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00651

Hom.:

Bravo

AF:

0.00462

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00788

AC:

956

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00775

EpiControl

AF:

0.00777

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

.;D;D

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.7

.;D;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

.;D;.

Sift4G

Uncertain

0.031

.;D;.

Polyphen

0.10

B;B;B

Vest4

0.64

MVP

0.74

MPC

0.39

ClinPred

0.059

GERP RS

0.39

Varity_R

0.43

gMVP

0.89

Mutation Taster

=89/11

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over