chr13-95034637-C-T

Position:

• chr13-95034637-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005845.5(ABCC4):​c.3838G>A​(p.Glu1280Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30564803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.3838G>A	p.Glu1280Lys	missense_variant	30/31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.3697G>A	p.Glu1233Lys	missense_variant	29/30		NP_001288758.1
ABCC4	XM_047430034.1	c.3709G>A	p.Glu1237Lys	missense_variant	30/31		XP_047285990.1
ABCC4	XM_047430035.1	c.3289G>A	p.Glu1097Lys	missense_variant	27/28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.3838G>A	p.Glu1280Lys	missense_variant	30/31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000494 AC: 6

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

May 27, 2022

The c.3838G>A (p.E1280K) alteration is located in exon 30 (coding exon 30) of the ABCC4 gene. This alteration results from a G to A substitution at nucleotide position 3838, causing the glutamic acid (E) at amino acid position 1280 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	.;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.37	.;T;.
Sift4G	Benign	0.42	.;T;.
Polyphen		0.0050	B;B;B
Vest4		0.78
MutPred		0.44		Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);.;
MVP		0.81
MPC		0.30
ClinPred		0.77	D
GERP RS		6.2
Varity_R		0.35
gMVP		0.71

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: rs769378898; hg19: chr13-95686891;