13-95206742-T-C

Variant names:

• chr13-95206742-T-C
• rs2274406
• NM_005845.5:c.951A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005845.5(ABCC4):​c.951A>G​(p.Arg317Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,613,596 control chromosomes in the GnomAD database, including 328,042 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 0.56 (24595 hom., cov: 32)
  • Exomes 𝑓: 0.64 (303447 hom.)
• Consequence: ABCC4 NM_005845.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 36 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.229 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.951A>G	p.Arg317Arg	synonymous_variant	Exon 8 of 31	ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.951A>G	p.Arg317Arg	synonymous_variant	Exon 8 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84548 AN: 151956 Hom.: 24601 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.557

GnomAD2 exomes AF: 0.602 AC: 151391 AN: 251296 AF XY: 0.610

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.641 AC: 937152 AN: 1461522 Hom.: 303447 Cov.: 50 AF XY: 0.642 AC XY: 466701 AN XY: 727102

African (AFR) AF: 0.358 AC: 11978 AN: 33470

American (AMR) AF: 0.548 AC: 24525 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13883 AN: 26132

East Asian (EAS) AF: 0.556 AC: 22060 AN: 39700

South Asian (SAS) AF: 0.638 AC: 55040 AN: 86248

European-Finnish (FIN) AF: 0.637 AC: 34037 AN: 53410

Middle Eastern (MID) AF: 0.524 AC: 3024 AN: 5768

European-Non Finnish (NFE) AF: 0.662 AC: 735823 AN: 1111688

Other (OTH) AF: 0.609 AC: 36782 AN: 60382

GnomAD4 genome AF: 0.556 AC: 84561 AN: 152074 Hom.: 24595 Cov.: 32 AF XY: 0.553 AC XY: 41087 AN XY: 74348

African (AFR) AF: 0.371 AC: 15401 AN: 41482

American (AMR) AF: 0.557 AC: 8518 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1888 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2768 AN: 5142

South Asian (SAS) AF: 0.622 AC: 2994 AN: 4810

European-Finnish (FIN) AF: 0.625 AC: 6608 AN: 10576

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44477 AN: 67980

Other (OTH) AF: 0.552 AC: 1166 AN: 2114

Alfa AF: 0.612 Hom.: 73921

Bravo AF: 0.539

Asia WGS AF: 0.538 AC: 1871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		0.23
Mutation Taster		=79/21	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: rs2274406; hg19: chr13-95858996; COSMIC: COSV65309334;