rs11568696

Variant names:

• chr13-95166374-T-C
• rs11568696
• NM_005845.5:c.1825-7A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005845.5(ABCC4):​c.1825-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,607,130 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (18 hom.)
• Consequence: ABCC4 NM_005845.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003710
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-95166374-T-C is Benign according to our data. Variant chr13-95166374-T-C is described in ClinVar as Benign. ClinVar VariationId is 717315.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00719 (1095/152296) while in subpopulation AFR AF = 0.0251 (1043/41570). AF 95% confidence interval is 0.0238. There are 13 homozygotes in GnomAd4. There are 516 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.1825-7A>G		splice_region intron	N/A	NP_005836.2
	ABCC4	NM_001301829.2		c.1825-7A>G		splice_region intron	N/A	NP_001288758.1
	ABCC4	NM_001105515.3		c.1825-7A>G		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.1825-7A>G		splice_region intron	N/A	ENSP00000494609.1
	ABCC4	ENST00000629385.1	TSL:1	c.1825-7A>G		splice_region intron	N/A	ENSP00000487081.1
	ABCC4	ENST00000646439.1		c.1825-7A>G		splice_region intron	N/A	ENSP00000494751.1

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1093 AN: 152178 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.000103

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00174 AC: 430 AN: 247608 AF XY: 0.00132

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.000996

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.000733 AC: 1066 AN: 1454834 Hom.: 18 Cov.: 29 AF XY: 0.000648 AC XY: 469 AN XY: 723984

African (AFR) AF: 0.0272 AC: 899 AN: 33096

American (AMR) AF: 0.00102 AC: 45 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000702 AC: 6 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00115 AC: 5 AN: 4354

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108598

Other (OTH) AF: 0.00168 AC: 101 AN: 59992

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152296 Hom.: 13 Cov.: 32 AF XY: 0.00693 AC XY: 516 AN XY: 74462

African (AFR) AF: 0.0251 AC: 1043 AN: 41570

American (AMR) AF: 0.00196 AC: 30 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00352 Hom.: 3

Bravo AF: 0.00841

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.58
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs11568696; hg19: chr13-95818628;