NM_005845.5:c.3211G>A

Variant names:

• chr13-95062859-C-T
• rs11568653
• NM_005845.5:c.3211G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005845.5(ABCC4):​c.3211G>A​(p.Val1071Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000325 in 1,601,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict 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 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ABCC4 NM_005845.5 missense, splice_region
• Scores: Splicing: ADA: 0.9175
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0134314).

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.3211G>A	p.Val1071Ile	missense splice_region	Exon 26 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.3070G>A	p.Val1024Ile	missense splice_region	Exon 25 of 30	NP_001288758.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.3211G>A	p.Val1071Ile	missense splice_region	Exon 26 of 31	ENSP00000494609.1
	ABCC4	ENST00000967420.1		c.3211G>A	p.Val1071Ile	missense splice_region	Exon 26 of 31	ENSP00000637479.1
	ABCC4	ENST00000967421.1		c.3208G>A	p.Val1070Ile	missense splice_region	Exon 26 of 31	ENSP00000637480.1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 255 AN: 147008 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000349

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00101

GnomAD2 exomes AF: 0.000536 AC: 126 AN: 234958 AF XY: 0.000370

Gnomad AFR exome AF: 0.00690

Gnomad AMR exome AF: 0.000548

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000537

GnomAD4 exome AF: 0.000182 AC: 264 AN: 1454254 Hom.: 0 Cov.: 38 AF XY: 0.000149 AC XY: 108 AN XY: 722964

African (AFR) AF: 0.00644 AC: 213 AN: 33100

American (AMR) AF: 0.000440 AC: 19 AN: 43154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 84080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109396

Other (OTH) AF: 0.000416 AC: 25 AN: 60060

GnomAD4 genome AF: 0.00174 AC: 256 AN: 147128 Hom.: 0 Cov.: 31 AF XY: 0.00167 AC XY: 119 AN XY: 71372

African (AFR) AF: 0.00620 AC: 246 AN: 39704

American (AMR) AF: 0.000348 AC: 5 AN: 14348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

South Asian (SAS) AF: 0.000226 AC: 1 AN: 4426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9894

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

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67122

Other (OTH) AF: 0.000998 AC: 2 AN: 2004

Alfa AF: 0.000610 Hom.: 2

Bravo AF: 0.00215

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.53	N
PhyloP100		4.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.37
Sift	Benign	0.30	T
Sift4G	Benign	0.39	T
Polyphen		0.058	B
Vest4		0.13
MVP		0.57
MPC		0.20
ClinPred		0.0084	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.54
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.10		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: rs11568653; hg19: chr13-95715113;