13-95062787-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005845.5(ABCC4):c.3283G>A(p.Glu1095Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2474184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC4	NM_005845.5	c.3283G>A	p.Glu1095Lys	missense_variant	26/31	ENST00000645237.2
ABCC4	NM_001301829.2	c.3142G>A	p.Glu1048Lys	missense_variant	25/30
ABCC4	XM_047430034.1	c.3154G>A	p.Glu1052Lys	missense_variant	26/31
ABCC4	XM_047430035.1	c.2734G>A	p.Glu912Lys	missense_variant	23/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC4	ENST00000645237.2	c.3283G>A	p.Glu1095Lys	missense_variant	26/31		NM_005845.5	P1
ABCC4	ENST00000646439.1	c.3142G>A	p.Glu1048Lys	missense_variant	25/30
ABCC4	ENST00000643051.1	c.*908G>A		3_prime_UTR_variant, NMD_transcript_variant	27/33
ABCC4	ENST00000643842.1	c.*3329G>A		3_prime_UTR_variant, NMD_transcript_variant	27/32

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151874 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251380 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461816 Hom.: 0 Cov.: 38 AF XY: 0.0000385 AC XY: 28 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151874 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74150

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.3283G>A (p.E1095K) alteration is located in exon 26 (coding exon 26) of the ABCC4 gene. This alteration results from a G to A substitution at nucleotide position 3283, causing the glutamic acid (E) at amino acid position 1095 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Benign	0.74	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Polyphen		0.013	B;B;B
Vest4		0.23
MutPred		0.53		Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);.;
MVP		0.73
MPC		0.27
ClinPred		0.058	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.61

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: rs751961590; hg19: chr13-95715041; COSMIC: COSV105312725;