13-95021640-G-A

Position:

• chr13-95021640-G-A

Variant summary

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

The NM_005845.5(ABCC4):​c.3913C>T​(p.His1305Tyr) 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 benign outcome for this variant. 16/21 in silico tools predict 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: 1.78

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 (HGNC:):

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=0.10181764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.3913C>T	p.His1305Tyr	missense_variant	31/31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.3772C>T	p.His1258Tyr	missense_variant	30/30		NP_001288758.1
ABCC4	XM_047430034.1	c.3784C>T	p.His1262Tyr	missense_variant	31/31		XP_047285990.1
ABCC4	XM_047430035.1	c.3364C>T	p.His1122Tyr	missense_variant	28/28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.3913C>T	p.His1305Tyr	missense_variant	31/31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jun 17, 2024

The c.3913C>T (p.H1305Y) alteration is located in exon 31 (coding exon 31) of the ABCC4 gene. This alteration results from a C to T substitution at nucleotide position 3913, causing the histidine (H) at amino acid position 1305 to be replaced by a tyrosine (Y). 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	0.067
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.4
DANN	Benign	0.50
DEOGEN2	Benign	0.078	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.36	.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.83	L;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	.;N;.
REVEL	Benign	0.20
Sift	Benign	0.060	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0010	B;B;B
Vest4		0.081
MutPred		0.49		Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);.;
MVP		0.59
MPC		0.27
ClinPred		0.080	T
GERP RS		1.9
Varity_R		0.026
gMVP		0.59

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: rs2031089372; hg19: chr13-95673894;