chr13-95053126-G-A

Variant names:

• chr13-95053126-G-A
• rs11568644
• NM_005845.5:c.3425C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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 (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.44
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• qualitative platelet defect

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 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 VariationId is 713177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005845.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.3425C>T	p.Thr1142Met	missense	Exon 27 of 31	NP_005836.2
	ABCC4	NM_001301829.2		c.3284C>T	p.Thr1095Met	missense	Exon 26 of 30	NP_001288758.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.3425C>T	p.Thr1142Met	missense	Exon 27 of 31	ENSP00000494609.1
	ABCC4	ENST00000967420.1		c.3425C>T	p.Thr1142Met	missense	Exon 27 of 31	ENSP00000637479.1
	ABCC4	ENST00000967421.1		c.3422C>T	p.Thr1141Met	missense	Exon 27 of 31	ENSP00000637480.1

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

GnomAD2 exomes AF: 0.00665 AC: 1672 AN: 251430 AF XY: 0.00743

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 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

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 256 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0129 AC: 1112 AN: 86252

European-Finnish (FIN) AF: 0.0172 AC: 920 AN: 53416

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.00622 AC: 6915 AN: 1111860

Other (OTH) AF: 0.00566 AC: 342 AN: 60386

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

African (AFR) AF: 0.000722 AC: 30 AN: 41546

American (AMR) AF: 0.00144 AC: 22 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4816

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00675 AC: 459 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00547 Hom.: 8

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.53
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.68	P
Vest4		0.23
MVP		0.92
MPC		0.82
ClinPred		0.047	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.46
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs11568644; hg19: chr13-95705380; COSMIC: COSV105928339;