rs11568705

chr13-95194891-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_005845.5(ABCC4):c.1208C>T(p.Pro403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,614,054 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.907

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076387823).
• BP6: Variant 13-95194891-G-A is Benign according to our data. Variant chr13-95194891-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041539.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC4	NM_005845.5	c.1208C>T	p.Pro403Leu	missense_variant	9/31	ENST00000645237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC4	ENST00000645237.2	c.1208C>T	p.Pro403Leu	missense_variant	9/31		NM_005845.5	P1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 229 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000505 AC: 127 AN: 251398 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135866

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000397 AC: 581 AN: 1461818 Hom.: 1 Cov.: 31 AF XY: 0.000392 AC XY: 285 AN XY: 727218

Gnomad4 AFR exome AF: 0.00409

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74418

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.00210

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ABCC4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	14
Dann	Benign	0.57
DEOGEN2	Benign	0.26	T;T;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.061	N
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.0076	T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
Polyphen		0.0060	B;B;B;.;.;.
Vest4		0.069, 0.079, 0.092
MVP		0.66
MPC		0.24
ClinPred		0.018	T
GERP RS		1.8
Varity_R		0.024
gMVP		0.54

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: rs11568705; hg19: chr13-95847145; COSMIC: COSV65313301;