NM_005845.5:c.2269G>A

Variant names:

• chr13-95163161-C-T
• rs3765534
• NM_005845.5:c.2269G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005845.5(ABCC4):​c.2269G>A​(p.Glu757Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,114 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.017 (583 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 68 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022514462).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.2269G>A	p.Glu757Lys	missense_variant	Exon 18 of 31	ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.2269G>A	p.Glu757Lys	missense_variant	Exon 18 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2041 AN: 152074 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0805

Gnomad SAS AF: 0.0492

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0231 AC: 5796 AN: 251036 AF XY: 0.0233

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.0429

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0652

Gnomad FIN exome AF: 0.00887

Gnomad NFE exome AF: 0.00984

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0167 AC: 24386 AN: 1460922 Hom.: 583 Cov.: 30 AF XY: 0.0176 AC XY: 12789 AN XY: 726784

African (AFR) AF: 0.00212 AC: 71 AN: 33466

American (AMR) AF: 0.0402 AC: 1793 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 143 AN: 26126

East Asian (EAS) AF: 0.112 AC: 4424 AN: 39642

South Asian (SAS) AF: 0.0504 AC: 4337 AN: 86122

European-Finnish (FIN) AF: 0.00977 AC: 522 AN: 53402

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5766

European-Non Finnish (NFE) AF: 0.0109 AC: 12150 AN: 1111376

Other (OTH) AF: 0.0151 AC: 910 AN: 60368

GnomAD4 genome AF: 0.0134 AC: 2041 AN: 152192 Hom.: 44 Cov.: 32 AF XY: 0.0144 AC XY: 1071 AN XY: 74414

African (AFR) AF: 0.00371 AC: 154 AN: 41526

American (AMR) AF: 0.0253 AC: 387 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.0805 AC: 417 AN: 5178

South Asian (SAS) AF: 0.0492 AC: 237 AN: 4814

European-Finnish (FIN) AF: 0.00839 AC: 89 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0103 AC: 702 AN: 68006

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0127 Hom.: 137

Bravo AF: 0.0141

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.0237 AC: 2874

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	3.8
DANN	Benign	0.47
DEOGEN2	Benign	0.25	T;T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.70	.;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;.;.;L
PhyloP100		0.046
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	.;N;.;N;.
REVEL	Benign	0.26
Sift	Benign	0.34	.;T;.;T;.
Sift4G	Benign	0.46	.;T;.;T;T
Polyphen		0.0010	B;B;B;.;.
Vest4		0.043, 0.092
MPC		0.26
ClinPred		0.00044	T
GERP RS		1.4
Varity_R		0.058
gMVP		0.45
Mutation Taster		=96/4	polymorphism (auto)

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: rs3765534; hg19: chr13-95815415; COSMIC: COSV65311705; COSMIC: COSV65311705;