rs11568644

chr13-95053126-G-Achr13-95053126-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005845.5(ABCC4):c.3425C>T(p.Thr1142Met) variant causes a missense change. The variant allele was found at a frequency of 0.00646 in 1,613,900 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts 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 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (54 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.44

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013533205).
• BP6: Variant 13-95053126-G-A is Benign according to our data. Variant chr13-95053126-G-A is described in ClinVar as [Benign]. Clinvar id is 713177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC4	NM_005845.5	c.3425C>T	p.Thr1142Met	missense_variant	27/31	ENST00000645237.2
ABCC4	NM_001301829.2	c.3284C>T	p.Thr1095Met	missense_variant	26/30
ABCC4	XM_047430034.1	c.3296C>T	p.Thr1099Met	missense_variant	27/31
ABCC4	XM_047430035.1	c.2876C>T	p.Thr959Met	missense_variant	24/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC4	ENST00000645237.2	c.3425C>T	p.Thr1142Met	missense_variant	27/31		NM_005845.5	P1

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152100 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00675

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00665 AC: 1672 AN: 251430 Hom.: 14 AF XY: 0.00743 AC XY: 1009 AN XY: 135882

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.00680

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00659 AC: 9634 AN: 1461682 Hom.: 54 Cov.: 31 AF XY: 0.00684 AC XY: 4971 AN XY: 727152

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00980

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00622

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152218 Hom.: 5 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74426

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.00675

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00573 Hom.: 5

Bravo AF: 0.00359

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00680 AC: 826

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00486

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

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
Polyphen		0.68	P;P;B
Vest4		0.23
MVP		0.92
MPC		0.82
ClinPred		0.047	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11568644; hg19: chr13-95705380; COSMIC: COSV105928339;