chr13-95062841-T-A

Position:

• chr13-95062841-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005845.5(ABCC4):​c.3229A>T​(p.Thr1077Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.3229A>T	p.Thr1077Ser	missense_variant	26/31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.3088A>T	p.Thr1030Ser	missense_variant	25/30		NP_001288758.1
ABCC4	XM_047430034.1	c.3100A>T	p.Thr1034Ser	missense_variant	26/31		XP_047285990.1
ABCC4	XM_047430035.1	c.2680A>T	p.Thr894Ser	missense_variant	23/28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.3229A>T	p.Thr1077Ser	missense_variant	26/31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 30

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

Oct 20, 2023

The c.3229A>T (p.T1077S) alteration is located in exon 26 (coding exon 26) of the ABCC4 gene. This alteration results from a A to T substitution at nucleotide position 3229, causing the threonine (T) at amino acid position 1077 to be replaced by a serine (S). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.015	N;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	.;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	.;D;.
Sift4G	Uncertain	0.0040	.;D;.
Polyphen		0.99	D;D;D
Vest4		0.75
MutPred		0.77		Gain of disorder (P = 0.0242);Gain of disorder (P = 0.0242);.;
MVP		0.89
MPC		0.67
ClinPred		0.96	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-95715095;