chr13-95247100-A-G

Position:

• chr13-95247100-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005845.5(ABCC4):​c.186-5T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003013
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.186-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.186-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_005845.5	ENSP00000494609	P1

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

GnomAD3 exomes AF: 0.315 AC: 77384 AN: 245454 Hom.: 13188 AF XY: 0.317 AC XY: 42003 AN XY: 132542

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 SAS exome AF: 0.232

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

Gnomad4 AFR exome AF: 0.0746

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.407

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.325

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

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.309

Alfa AF: 0.344 Hom.: 15590

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.4
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs4148437; hg19: chr13-95899354; COSMIC: COSV65309787;