NM_005845.5:c.3712A>T

Variant names:

• chr13-95043705-T-A
• rs1019370520
• NM_005845.5:c.3712A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005845.5(ABCC4):​c.3712A>T​(p.Ile1238Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.3712A>T	p.Ile1238Phe	missense_variant	Exon 29 of 31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.3571A>T	p.Ile1191Phe	missense_variant	Exon 28 of 30		NP_001288758.1
ABCC4	XM_047430034.1	c.3583A>T	p.Ile1195Phe	missense_variant	Exon 29 of 31		XP_047285990.1
ABCC4	XM_047430035.1	c.3163A>T	p.Ile1055Phe	missense_variant	Exon 26 of 28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.3712A>T	p.Ile1238Phe	missense_variant	Exon 29 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.088	D
MutationAssessor	Pathogenic	4.0	H;H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	.;D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0010	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.81		Loss of stability (P = 0.0894);Loss of stability (P = 0.0894);.;
MVP		0.79
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1019370520; hg19: chr13-95695959;