rs9282570

chr13-95163200-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005845.5(ABCC4):c.2230A>G(p.Met744Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,612,506 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.679

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021744668).
• BP6: Variant 13-95163200-T-C is Benign according to our data. Variant chr13-95163200-T-C is described in ClinVar as [Benign]. Clinvar id is 786614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1806/152304) while in subpopulation AFR AF= 0.0404 (1679/41560). AF 95% confidence interval is 0.0388. There are 48 homozygotes in gnomad4. There are 857 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC4	NM_005845.5	c.2230A>G	p.Met744Val	missense_variant	18/31	ENST00000645237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC4	ENST00000645237.2	c.2230A>G	p.Met744Val	missense_variant	18/31		NM_005845.5	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1804 AN: 152186 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00331 AC: 829 AN: 250446 Hom.: 14 AF XY: 0.00256 AC XY: 347 AN XY: 135374

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00125 AC: 1818 AN: 1460202 Hom.: 36 Cov.: 30 AF XY: 0.00111 AC XY: 805 AN XY: 726448

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.0119 AC: 1806 AN: 152304 Hom.: 48 Cov.: 32 AF XY: 0.0115 AC XY: 857 AN XY: 74490

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00236 Hom.: 16

Bravo AF: 0.0132

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00384 AC: 466

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.73
Dann	Benign	0.31
DEOGEN2	Benign	0.12	T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.060	N;N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
Polyphen		0.0	B;B;B;.;.
Vest4		0.079, 0.091, 0.075
MVP		0.39
MPC		0.24
ClinPred		0.00094	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.027
gMVP		0.37

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: rs9282570; hg19: chr13-95815454;