rs11568669

Variant names:

• chr13-95186754-T-C
• rs11568669
• NM_005845.5:c.1492A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000645237.2(ABCC4):​c.1492A>G​(p.Lys498Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,614,182 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: ABCC4 ENST00000645237.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28
• Publications: 8 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013015598).
• BP6: Variant 13-95186754-T-C is Benign according to our data. Variant chr13-95186754-T-C is described in ClinVar as Benign. ClinVar VariationId is 776802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000645237.2. 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.1492A>G	p.Lys498Glu	missense	Exon 11 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.1492A>G	p.Lys498Glu	missense	Exon 11 of 30	NP_001288758.1
	ABCC4	NM_001105515.3		c.1492A>G	p.Lys498Glu	missense	Exon 11 of 21	NP_001098985.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.1492A>G	p.Lys498Glu	missense	Exon 11 of 31	ENSP00000494609.1
	ABCC4	ENST00000629385.1	TSL:1	c.1492A>G	p.Lys498Glu	missense	Exon 11 of 21	ENSP00000487081.1
	ABCC4	ENST00000646439.1		c.1492A>G	p.Lys498Glu	missense	Exon 11 of 30	ENSP00000494751.1

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 500 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00102 AC: 257 AN: 251400 AF XY: 0.000670

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000380 AC: 556 AN: 1461854 Hom.: 2 Cov.: 31 AF XY: 0.000303 AC XY: 220 AN XY: 727236

African (AFR) AF: 0.0119 AC: 400 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111988

Other (OTH) AF: 0.000911 AC: 55 AN: 60394

GnomAD4 genome AF: 0.00332 AC: 506 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00324 AC XY: 241 AN XY: 74494

African (AFR) AF: 0.0115 AC: 478 AN: 41582

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.00368

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.18	N
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.044
MVP		0.67
MPC		0.33
ClinPred		0.0090	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.69
Mutation Taster		=99/1	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: rs11568669; hg19: chr13-95839008;