chr13-95209550-A-G

Variant names:

• chr13-95209550-A-G
• rs899494
• NM_005845.5:c.669T>C

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.669T>C​(p.Ile223Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 1,613,874 control chromosomes in the GnomAD database, including 583,998 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 0.83 (52727 hom., cov: 34)
  • Exomes 𝑓: 0.85 (531271 hom.)
• Consequence: ABCC4 NM_005845.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 38 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=-0.81).
• BP7: Synonymous conserved (PhyloP=-2.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.669T>C	p.Ile223Ile	synonymous_variant	Exon 6 of 31	ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.669T>C	p.Ile223Ile	synonymous_variant	Exon 6 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126405 AN: 152102 Hom.: 52705 Cov.: 34

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.864

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.816

GnomAD2 exomes AF: 0.833 AC: 209004 AN: 251008 AF XY: 0.826

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.883

Gnomad ASJ exome AF: 0.736

Gnomad EAS exome AF: 0.788

Gnomad FIN exome AF: 0.853

Gnomad NFE exome AF: 0.859

Gnomad OTH exome AF: 0.825

GnomAD4 exome AF: 0.852 AC: 1244618 AN: 1461654 Hom.: 531271 Cov.: 47 AF XY: 0.848 AC XY: 616386 AN XY: 727132

African (AFR) AF: 0.788 AC: 26388 AN: 33478

American (AMR) AF: 0.877 AC: 39197 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 19427 AN: 26126

East Asian (EAS) AF: 0.792 AC: 31442 AN: 39686

South Asian (SAS) AF: 0.748 AC: 64494 AN: 86238

European-Finnish (FIN) AF: 0.852 AC: 45505 AN: 53416

Middle Eastern (MID) AF: 0.716 AC: 4127 AN: 5764

European-Non Finnish (NFE) AF: 0.867 AC: 963716 AN: 1111854

Other (OTH) AF: 0.833 AC: 50322 AN: 60382

GnomAD4 genome AF: 0.831 AC: 126473 AN: 152220 Hom.: 52727 Cov.: 34 AF XY: 0.828 AC XY: 61608 AN XY: 74450

African (AFR) AF: 0.792 AC: 32893 AN: 41518

American (AMR) AF: 0.856 AC: 13087 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2633 AN: 3468

East Asian (EAS) AF: 0.792 AC: 4110 AN: 5188

South Asian (SAS) AF: 0.747 AC: 3600 AN: 4820

European-Finnish (FIN) AF: 0.851 AC: 9027 AN: 10604

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58394 AN: 68008

Other (OTH) AF: 0.809 AC: 1711 AN: 2114

Alfa AF: 0.846 Hom.: 212233

Bravo AF: 0.830

Asia WGS AF: 0.773 AC: 2690 AN: 3478

EpiCase AF: 0.848

EpiControl AF: 0.848

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.34
DANN	Benign	0.58
PhyloP100		-2.5
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: rs899494; hg19: chr13-95861804; COSMIC: COSV65316381;