17-50656775-G-A

Position:

• chr17-50656775-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000285238.13(ABCC3):​c.296G>A​(p.Arg99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,976 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: ABCC3 ENST00000285238.13 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.134

Genes affected

ABCC3 (HGNC:54): (ATP binding cassette subfamily C member 3) 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. The specific function of this protein has not yet been determined; however, this protein may play a role in the transport of biliary and intestinal excretion of organic anions. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002481997).
• BP6: Variant 17-50656775-G-A is Benign according to our data. Variant chr17-50656775-G-A is described in ClinVar as [Benign]. Clinvar id is 768900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1623/152310) while in subpopulation AFR AF= 0.0367 (1523/41554). AF 95% confidence interval is 0.0351. There are 25 homozygotes in gnomad4. There are 770 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC3	NM_003786.4	c.296G>A	p.Arg99Gln	missense_variant	3/31	ENST00000285238.13	NP_003777.2
ABCC3	NM_001144070.2	c.296G>A	p.Arg99Gln	missense_variant	3/12		NP_001137542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC3	ENST00000285238.13	c.296G>A	p.Arg99Gln	missense_variant	3/31	1	NM_003786.4	ENSP00000285238	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 152192 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00270 AC: 678 AN: 250824 Hom.: 13 AF XY: 0.00196 AC XY: 265 AN XY: 135534

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00110 AC: 1613 AN: 1461666 Hom.: 29 Cov.: 31 AF XY: 0.00100 AC XY: 728 AN XY: 727128

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.0107 AC: 1623 AN: 152310 Hom.: 25 Cov.: 33 AF XY: 0.0103 AC XY: 770 AN XY: 74486

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00236 Hom.: 10

Bravo AF: 0.0111

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.059
Sift	Benign	0.59	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.020	B;B
Vest4		0.28
MVP		0.22
MPC		0.18
ClinPred		0.0048	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.10

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: rs35777968; hg19: chr17-48734136;