Genetic Variant ABCC4:p.Phe948Leu (chr13-95074287-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005845.5(ABCC4):c.2844T>A(p.Phe948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ABCC4
NM_005845.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.183

Publications

30 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5 link	c.2844T>A	p.Phe948Leu	missense_variant	Exon 23 of 31	ENST00000645237.2	NP_005836.2	O15439-1A8K2Q2
ABCC4	NM_001301829.2 link	c.2703T>A	p.Phe901Leu	missense_variant	Exon 22 of 30		NP_001288758.1	O15439-2A8K2Q2
ABCC4	XM_047430034.1 link	c.2715T>A	p.Phe905Leu	missense_variant	Exon 23 of 31		XP_047285990.1
ABCC4	XM_047430035.1 link	c.2295T>A	p.Phe765Leu	missense_variant	Exon 20 of 28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2 link	c.2844T>A	p.Phe948Leu	missense_variant	Exon 23 of 31		NM_005845.5	ENSP00000494609.1		O15439-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726950

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111860

Other (OTH)

AF:

0.00

AC:

AN:

60374

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

4.9

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.70

.;T;T

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.15

N;N;.

PhyloP100

-0.18

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

.;N;.

REVEL

Benign

0.28

Sift

Benign

0.19

.;T;.

Sift4G

Benign

0.45

.;T;.

Polyphen

0.0

B;B;B

Vest4

0.25

MutPred

0.71

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;

MVP

0.23

MPC

0.29

ClinPred

0.22

GERP RS

-3.7

Varity_R

0.23

gMVP

0.67

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: -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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over