rs1751034

Positions:

• chr13-95062722-C-G
• chr13-95062722-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.3348G>C	p.Lys1116Asn	missense_variant	26/31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.3207G>C	p.Lys1069Asn	missense_variant	25/30		NP_001288758.1
ABCC4	XM_047430034.1	c.3219G>C	p.Lys1073Asn	missense_variant	26/31		XP_047285990.1
ABCC4	XM_047430035.1	c.2799G>C	p.Lys933Asn	missense_variant	23/28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.3348G>C	p.Lys1116Asn	missense_variant	26/31		NM_005845.5	ENSP00000494609	P1
ABCC4	ENST00000646439.1	c.3207G>C	p.Lys1069Asn	missense_variant	25/30			ENSP00000494751
ABCC4	ENST00000643051.1	c.*973G>C		3_prime_UTR_variant, NMD_transcript_variant	27/33			ENSP00000495513
ABCC4	ENST00000643842.1	c.*3394G>C		3_prime_UTR_variant, NMD_transcript_variant	27/32			ENSP00000493861

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	0.57	N;N;.
MutationTaster	Benign	0.0000040	P;P
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;P;P
Vest4		0.22
MutPred		0.68		Loss of catalytic residue at M1117 (P = 0.0361);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1751034; hg19: chr13-95714976;