rs2274407

Variant names:

• chr13-95206781-C-A
• rs2274407
• NM_005845.5:c.912G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-95206781-C-A
• chr13-95206781-C-G
• chr13-95206781-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005845.5(ABCC4):​c.912G>T​(p.Lys304Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,613,542 control chromosomes in the GnomAD database, including 6,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 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 0.10 (1006 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5837 hom.)
• Consequence: ABCC4 NM_005845.5 missense, splice_region
• Scores: Splicing: ADA: 0.5090
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 65 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=0.0020405948).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.912G>T	p.Lys304Asn	missense_variant, splice_region_variant	Exon 8 of 31	ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.912G>T	p.Lys304Asn	missense_variant, splice_region_variant	Exon 8 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15803 AN: 152006 Hom.: 1004 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0972 AC: 24412 AN: 251164 AF XY: 0.0974

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0698

Gnomad OTH exome AF: 0.0944

GnomAD4 exome AF: 0.0802 AC: 117262 AN: 1461418 Hom.: 5837 Cov.: 35 AF XY: 0.0820 AC XY: 59601 AN XY: 727018

African (AFR) AF: 0.175 AC: 5844 AN: 33464

American (AMR) AF: 0.0919 AC: 4109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3483 AN: 26136

East Asian (EAS) AF: 0.219 AC: 8674 AN: 39688

South Asian (SAS) AF: 0.135 AC: 11633 AN: 86216

European-Finnish (FIN) AF: 0.0625 AC: 3337 AN: 53380

Middle Eastern (MID) AF: 0.113 AC: 654 AN: 5768

European-Non Finnish (NFE) AF: 0.0663 AC: 73719 AN: 1111668

Other (OTH) AF: 0.0962 AC: 5809 AN: 60374

GnomAD4 genome AF: 0.104 AC: 15809 AN: 152124 Hom.: 1006 Cov.: 32 AF XY: 0.102 AC XY: 7568 AN XY: 74392

African (AFR) AF: 0.167 AC: 6930 AN: 41502

American (AMR) AF: 0.0810 AC: 1239 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 460 AN: 3472

East Asian (EAS) AF: 0.175 AC: 903 AN: 5150

South Asian (SAS) AF: 0.144 AC: 693 AN: 4804

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10604

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.0683 AC: 4641 AN: 67996

Other (OTH) AF: 0.107 AC: 225 AN: 2106

Alfa AF: 0.0833 Hom.: 1505

Bravo AF: 0.108

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0711 AC: 274

ESP6500AA AF: 0.171 AC: 754

ESP6500EA AF: 0.0705 AC: 606

ExAC AF: 0.100 AC: 12165

Asia WGS AF: 0.179 AC: 626 AN: 3478

EpiCase AF: 0.0718

EpiControl AF: 0.0736

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;.;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0020	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;L;.
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	.;N;.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.044	.;D;.;T;.;.
Sift4G	Uncertain	0.042	.;D;.;D;D;.
Polyphen		0.086	B;B;B;.;.;.
Vest4		0.17, 0.19, 0.15
MutPred		0.18		Loss of MoRF binding (P = 0.0428);Loss of MoRF binding (P = 0.0428);Loss of MoRF binding (P = 0.0428);.;Loss of MoRF binding (P = 0.0428);.;
MPC		0.30
ClinPred		0.021	T
GERP RS		1.7
Varity_R		0.14
gMVP		0.64
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.51
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.070		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: rs2274407; hg19: chr13-95859035; COSMIC: COSV65309342;