NM_005845.5:c.2560G>T

Variant names:

• chr13-95083266-C-A
• rs11568694
• NM_005845.5:c.2560G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005845.5(ABCC4):​c.2560G>T​(p.Val854Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,613,880 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (106 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 21 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 (MetaRNN=0.006900698).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00511 (778/152212) while in subpopulation SAS AF = 0.0264 (127/4804). AF 95% confidence interval is 0.0227. There are 2 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.2560G>T	p.Val854Phe	missense	Exon 21 of 31	NP_005836.2	O15439-1
	ABCC4	NM_001301829.2		c.2419G>T	p.Val807Phe	missense	Exon 20 of 30	NP_001288758.1	O15439-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.2560G>T	p.Val854Phe	missense	Exon 21 of 31	ENSP00000494609.1	O15439-1
	ABCC4	ENST00000967420.1		c.2560G>T	p.Val854Phe	missense	Exon 21 of 31	ENSP00000637479.1
	ABCC4	ENST00000967421.1		c.2557G>T	p.Val853Phe	missense	Exon 21 of 31	ENSP00000637480.1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 777 AN: 152094 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00706

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00758 AC: 1901 AN: 250856 AF XY: 0.00906

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.00686

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00808 AC: 11811 AN: 1461668 Hom.: 106 Cov.: 31 AF XY: 0.00891 AC XY: 6479 AN XY: 727138

African (AFR) AF: 0.000777 AC: 26 AN: 33466

American (AMR) AF: 0.00322 AC: 144 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 107 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0303 AC: 2613 AN: 86240

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53418

Middle Eastern (MID) AF: 0.00903 AC: 52 AN: 5758

European-Non Finnish (NFE) AF: 0.00747 AC: 8309 AN: 1111870

Other (OTH) AF: 0.00835 AC: 504 AN: 60388

GnomAD4 genome AF: 0.00511 AC: 778 AN: 152212 Hom.: 2 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74410

African (AFR) AF: 0.00135 AC: 56 AN: 41540

American (AMR) AF: 0.00458 AC: 70 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0264 AC: 127 AN: 4804

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68014

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00651 Hom.: 15

Bravo AF: 0.00462

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00788 AC: 956

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00775

EpiControl AF: 0.00777

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.031	D
Polyphen		0.10	B
Vest4		0.64
MVP		0.74
MPC		0.39
ClinPred		0.059	T
GERP RS		0.39
Varity_R		0.43
gMVP		0.89
Mutation Taster		=89/11	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: rs11568694; hg19: chr13-95735520; COSMIC: COSV65310719;