rs11568704

Variant names:

• chr13-95034701-C-T
• rs11568704
• NM_005845.5:c.3774G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_005845.5(ABCC4):​c.3774G>A​(p.Pro1258Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,614,154 control chromosomes in the GnomAD database, including 48 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 0.0099 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: ABCC4 NM_005845.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.86
• Publications: 5 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=-0.67).
• BP7: Synonymous conserved (PhyloP=-4.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00992 (1510/152282) while in subpopulation AFR AF = 0.0341 (1419/41562). AF 95% confidence interval is 0.0327. There are 31 homozygotes in GnomAd4. There are 748 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005845.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.3774G>A	p.Pro1258Pro	synonymous	Exon 30 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.3633G>A	p.Pro1211Pro	synonymous	Exon 29 of 30	NP_001288758.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.3774G>A	p.Pro1258Pro	synonymous	Exon 30 of 31	ENSP00000494609.1
	ABCC4	ENST00000967420.1		c.3798G>A	p.Pro1266Pro	synonymous	Exon 30 of 31	ENSP00000637479.1
	ABCC4	ENST00000967421.1		c.3771G>A	p.Pro1257Pro	synonymous	Exon 30 of 31	ENSP00000637480.1

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1496 AN: 152164 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00259 AC: 650 AN: 251418 AF XY: 0.00198

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00111 AC: 1619 AN: 1461872 Hom.: 17 Cov.: 31 AF XY: 0.000936 AC XY: 681 AN XY: 727240

African (AFR) AF: 0.0354 AC: 1184 AN: 33480

American (AMR) AF: 0.00199 AC: 89 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 173 AN: 1112008

Other (OTH) AF: 0.00225 AC: 136 AN: 60396

GnomAD4 genome AF: 0.00992 AC: 1510 AN: 152282 Hom.: 31 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74438

African (AFR) AF: 0.0341 AC: 1419 AN: 41562

American (AMR) AF: 0.00386 AC: 59 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00414 Hom.: 28

Bravo AF: 0.0112

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.0
DANN	Benign	0.38
PhyloP100		-4.9
Mutation Taster		=98/2	polymorphism

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: rs11568704; hg19: chr13-95686955;