chr13-95062722-C-G

Variant names:

• chr13-95062722-C-G
• rs1751034
• NM_005845.5:c.3348G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005845.5(ABCC4):​c.3348G>C​(p.Lys1116Asn) variant causes a missense 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.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• Publications: 61 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.3348G>C	p.Lys1116Asn	missense	Exon 26 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.3207G>C	p.Lys1069Asn	missense	Exon 25 of 30	NP_001288758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.3348G>C	p.Lys1116Asn	missense	Exon 26 of 31	ENSP00000494609.1
	ABCC4	ENST00000646439.1		c.3207G>C	p.Lys1069Asn	missense	Exon 25 of 30	ENSP00000494751.1
	ABCC4	ENST00000643051.1		n.*973G>C		non_coding_transcript_exon	Exon 27 of 33	ENSP00000495513.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461634 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 147837

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	0.57	N
PhyloP100		0.42
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		0.87	P
Vest4		0.22
MutPred		0.68		Loss of catalytic residue at M1117 (P = 0.0361)
MVP		0.71
MPC		0.40
ClinPred		0.99	D
GERP RS		0.54
Varity_R		0.75
gMVP		0.81
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1751034; hg19: chr13-95714976;