NM_005845.5:c.912G>T

Variant names:

• chr13-95206781-C-A
• rs2274407
• NM_005845.5:c.912G>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. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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: 67 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.

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.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 31	NP_005836.2	O15439-1
	ABCC4	NM_001301829.2		c.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 30	NP_001288758.1	O15439-2
	ABCC4	NM_001105515.3		c.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 21	NP_001098985.1	O15439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 31	ENSP00000494609.1	O15439-1
	ABCC4	ENST00000629385.1	TSL:1	c.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 21	ENSP00000487081.1	O15439-3
	ABCC4	ENST00000967420.1		c.912G>T	p.Lys304Asn	missense splice_region	Exon 8 of 31	ENSP00000637479.1

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 v4.9

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
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.044	D
Sift4G	Uncertain	0.042	D
Polyphen		0.086	B
Vest4		0.17
MutPred		0.18		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;