NM_005845.5:c.2269G>T

Variant names:

• chr13-95163161-C-A
• rs3765534
• NM_005845.5:c.2269G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005845.5(ABCC4):​c.2269G>T​(p.Glu757*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC4 NM_005845.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 68 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2269G>T	p.Glu757*	stop_gained	Exon 18 of 31	NP_005836.2	O15439-1
	ABCC4	NM_001301829.2		c.2128G>T	p.Glu710*	stop_gained	Exon 17 of 30	NP_001288758.1	O15439-2
	ABCC4	NM_001105515.3		c.2269G>T	p.Glu757*	stop_gained	Exon 18 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.2269G>T	p.Glu757*	stop_gained	Exon 18 of 31	ENSP00000494609.1	O15439-1
	ABCC4	ENST00000629385.1	TSL:1	c.2269G>T	p.Glu757*	stop_gained	Exon 18 of 21	ENSP00000487081.1	O15439-3
	ABCC4	ENST00000967420.1		c.2269G>T	p.Glu757*	stop_gained	Exon 18 of 31	ENSP00000637479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 137

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Benign	0.95
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.046
Vest4		0.85
GERP RS		1.4
Mutation Taster		=10/190	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3765534; hg19: chr13-95815415;