13-95074264-C-G

Variant names:

• chr13-95074264-C-G
• rs11568707
• NM_005845.5:c.2867G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005845.5(ABCC4):​c.2867G>C​(p.Cys956Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78
• Publications: 7 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.2867G>C	p.Cys956Ser	missense_variant	Exon 23 of 31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.2726G>C	p.Cys909Ser	missense_variant	Exon 22 of 30		NP_001288758.1
ABCC4	XM_047430034.1	c.2738G>C	p.Cys913Ser	missense_variant	Exon 23 of 31		XP_047285990.1
ABCC4	XM_047430035.1	c.2318G>C	p.Cys773Ser	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	c.2867G>C	p.Cys956Ser	missense_variant	Exon 23 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		5.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.0	.;D;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;.
Sift4G	Pathogenic	0.0	.;T;.
Vest4		0.0
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.80
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs11568707; hg19: chr13-95726518;