rs2274405

Variant names:

• chr13-95206724-T-C
• rs2274405
• NM_005845.5:c.969A>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.969A>G​(p.Ser323Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,838 control chromosomes in the GnomAD database, including 345,794 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 0.65 (32286 hom., cov: 32)
  • Exomes 𝑓: 0.65 (313508 hom.)
• Consequence: ABCC4 NM_005845.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.42
• Publications: 44 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=-0.9).
• BP7: Synonymous conserved (PhyloP=-5.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.969A>G	p.Ser323Ser	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.969A>G	p.Ser323Ser	synonymous_variant	Exon 8 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98833 AN: 151904 Hom.: 32278 Cov.: 32

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.630 AC: 158274 AN: 251294 AF XY: 0.631

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.527

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.653 AC: 955257 AN: 1461816 Hom.: 313508 Cov.: 57 AF XY: 0.653 AC XY: 474787 AN XY: 727220

African (AFR) AF: 0.688 AC: 23023 AN: 33476

American (AMR) AF: 0.573 AC: 25608 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 14164 AN: 26134

East Asian (EAS) AF: 0.557 AC: 22119 AN: 39698

South Asian (SAS) AF: 0.644 AC: 55551 AN: 86258

European-Finnish (FIN) AF: 0.637 AC: 34040 AN: 53408

Middle Eastern (MID) AF: 0.564 AC: 3252 AN: 5768

European-Non Finnish (NFE) AF: 0.665 AC: 739159 AN: 1111954

Other (OTH) AF: 0.635 AC: 38341 AN: 60396

GnomAD4 genome AF: 0.650 AC: 98877 AN: 152022 Hom.: 32286 Cov.: 32 AF XY: 0.644 AC XY: 47829 AN XY: 74298

African (AFR) AF: 0.689 AC: 28551 AN: 41456

American (AMR) AF: 0.601 AC: 9196 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1927 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2773 AN: 5136

South Asian (SAS) AF: 0.630 AC: 3032 AN: 4814

European-Finnish (FIN) AF: 0.626 AC: 6610 AN: 10556

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44723 AN: 67984

Other (OTH) AF: 0.619 AC: 1308 AN: 2112

Alfa AF: 0.651 Hom.: 135163

Bravo AF: 0.647

Asia WGS AF: 0.556 AC: 1937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.077
DANN	Benign	0.40
PhyloP100		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2274405; hg19: chr13-95858978; COSMIC: COSV65309326;