13-95021686-GAA-GAAA

Variant names:

• chr13-95021686-G-GA
• rs4148550
• NM_005845.5:c.3871-5dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_005845.5(ABCC4):​c.3871-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,223,308 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: ABCC4 NM_005845.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0710
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0128) population. However there is too low homozygotes in high coverage region: (expected more than 34, got 0).
• BP6: Variant 13-95021686-G-GA is Benign according to our data. Variant chr13-95021686-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 3059729.Status of the report is no_assertion_criteria_provided, 0 stars.

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.3871-5dupT		splice_region intron	N/A	NP_005836.2	O15439-1
	ABCC4	NM_001301829.2		c.3730-5dupT		splice_region intron	N/A	NP_001288758.1	O15439-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.3871-5_3871-4insT		splice_region intron	N/A	ENSP00000494609.1	O15439-1
	ABCC4	ENST00000967420.1		c.3895-5_3895-4insT		splice_region intron	N/A	ENSP00000637479.1
	ABCC4	ENST00000967421.1		c.3868-5_3868-4insT		splice_region intron	N/A	ENSP00000637480.1

Frequencies

GnomAD3 genomes AF: 0.0000740 AC: 11 AN: 148708 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000893

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00920 AC: 1430 AN: 155452 AF XY: 0.00825

Gnomad AFR exome AF: 0.00848

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.00989

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00486

Gnomad NFE exome AF: 0.00732

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0122 AC: 13069 AN: 1074514 Hom.: 0 Cov.: 25 AF XY: 0.0115 AC XY: 6163 AN XY: 536510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0141 AC: 329 AN: 23396

American (AMR) AF: 0.0127 AC: 382 AN: 30030

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 194 AN: 18820

East Asian (EAS) AF: 0.00668 AC: 203 AN: 30396

South Asian (SAS) AF: 0.0110 AC: 657 AN: 59898

European-Finnish (FIN) AF: 0.00415 AC: 176 AN: 42380

Middle Eastern (MID) AF: 0.00751 AC: 35 AN: 4658

European-Non Finnish (NFE) AF: 0.0129 AC: 10570 AN: 820354

Other (OTH) AF: 0.0117 AC: 523 AN: 44582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000739 AC: 11 AN: 148794 Hom.: 0 Cov.: 33 AF XY: 0.0000967 AC XY: 7 AN XY: 72392

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40506

American (AMR) AF: 0.0000670 AC: 1 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.000591 AC: 3 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000894 AC: 6 AN: 67146

Other (OTH) AF: 0.00 AC: 0 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000136622), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0293 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ABCC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.071
Mutation Taster		=97/3	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: rs4148550; hg19: chr13-95673940; COSMIC: COSV104688701;