chr13-95247100-A-G

Variant names:

• chr13-95247100-A-G
• rs4148437
• NM_005845.5:c.186-5T>C

Variant summary

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

The NM_005845.5(ABCC4):​c.186-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,607,292 control chromosomes in the GnomAD database, including 98,841 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (7182 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91659 hom.)
• Consequence: ABCC4 NM_005845.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003013
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 19 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 (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.186-5T>C		splice_region intron	N/A	NP_005836.2
	ABCC4	NM_001301829.2		c.186-5T>C		splice_region intron	N/A	NP_001288758.1
	ABCC4	NM_001105515.3		c.186-5T>C		splice_region intron	N/A	NP_001098985.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.186-5T>C		splice_region intron	N/A	ENSP00000494609.1
	ABCC4	ENST00000629385.1	TSL:1	c.186-5T>C		splice_region intron	N/A	ENSP00000487081.1
	ABCC4	ENST00000646439.1		c.186-5T>C		splice_region intron	N/A	ENSP00000494751.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42274 AN: 151992 Hom.: 7180 Cov.: 32

Gnomad AFR AF: 0.0871

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.315 AC: 77384 AN: 245454 AF XY: 0.317

Gnomad AFR exome AF: 0.0803

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.347 AC: 505008 AN: 1455182 Hom.: 91659 Cov.: 34 AF XY: 0.344 AC XY: 249303 AN XY: 723854

African (AFR) AF: 0.0746 AC: 2460 AN: 32954

American (AMR) AF: 0.337 AC: 14506 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8020 AN: 25868

East Asian (EAS) AF: 0.140 AC: 5558 AN: 39670

South Asian (SAS) AF: 0.232 AC: 19689 AN: 84686

European-Finnish (FIN) AF: 0.407 AC: 21692 AN: 53300

Middle Eastern (MID) AF: 0.254 AC: 1454 AN: 5728

European-Non Finnish (NFE) AF: 0.371 AC: 412103 AN: 1109780

Other (OTH) AF: 0.325 AC: 19526 AN: 60100

GnomAD4 genome AF: 0.278 AC: 42269 AN: 152110 Hom.: 7182 Cov.: 32 AF XY: 0.281 AC XY: 20878 AN XY: 74346

African (AFR) AF: 0.0869 AC: 3607 AN: 41524

American (AMR) AF: 0.329 AC: 5033 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1098 AN: 3472

East Asian (EAS) AF: 0.178 AC: 921 AN: 5180

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4818

European-Finnish (FIN) AF: 0.421 AC: 4444 AN: 10558

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24882 AN: 67962

Other (OTH) AF: 0.309 AC: 653 AN: 2112

Alfa AF: 0.338 Hom.: 18478

Bravo AF: 0.267

Asia WGS AF: 0.207 AC: 721 AN: 3478

EpiCase AF: 0.363

EpiControl AF: 0.360

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.4
DANN	Benign	0.70
PhyloP100		0.25
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.13		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: rs4148437; hg19: chr13-95899354; COSMIC: COSV65309787;