1-93996081-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):c.6816+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,605,520 control chromosomes in the GnomAD database, including 7,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3448 hom., cov: 32)
  • Exomes 𝑓: 0.048 (4197 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.268

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated 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 intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-93996081-C-G is Benign according to our data. Variant chr1-93996081-C-G is described in ClinVar as [Benign]. Clinvar id is 255927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6816+28G>C		intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.6594+28G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6816+28G>C		intron_variant		1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21538 AN: 152042 Hom.: 3441 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0652 AC: 16307 AN: 250004 Hom.: 1639 AF XY: 0.0582 AC XY: 7860 AN XY: 135112

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.0270

Gnomad SAS exome AF: 0.0498

Gnomad FIN exome AF: 0.00590

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0484 AC: 70375 AN: 1453360 Hom.: 4197 Cov.: 30 AF XY: 0.0476 AC XY: 34452 AN XY: 723506

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0702

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.0504

Gnomad4 FIN exome AF: 0.00686

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0683

GnomAD4 genome AF: 0.142 AC: 21579 AN: 152160 Hom.: 3448 Cov.: 32 AF XY: 0.137 AC XY: 10205 AN XY: 74404

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.0843

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.0408

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0896 Hom.: 290

Bravo AF: 0.160

Asia WGS AF: 0.0630 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.4
Dann	Benign	0.39

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: rs6666559; hg19: chr1-94461637;