1-94083473-A-G

Position:

• chr1-94083473-A-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.769-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,535,706 control chromosomes in the GnomAD database, including 67,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4975 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62242 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.649

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]

ABCA4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-94083473-A-G is Benign according to our data. Variant chr1-94083473-A-G is described in ClinVar as [Benign]. Clinvar id is 99507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.769-32T>C		intron_variant		ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.769-32T>C		intron_variant
LOC124904222	XR_007066231.1	n.203-256A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.769-32T>C		intron_variant		1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.769-32T>C		intron_variant				ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36500 AN: 151826 Hom.: 4969 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.245 AC: 60567 AN: 247468 Hom.: 7955 AF XY: 0.244 AC XY: 32808 AN XY: 134412

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.293 AC: 405486 AN: 1383762 Hom.: 62242 Cov.: 25 AF XY: 0.289 AC XY: 199975 AN XY: 693042

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.240 AC: 36524 AN: 151944 Hom.: 4975 Cov.: 32 AF XY: 0.237 AC XY: 17581 AN XY: 74286

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.254

Alfa AF: 0.181 Hom.: 588

Bravo AF: 0.235

Asia WGS AF: 0.188 AC: 654 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs526016; hg19: chr1-94549029; COSMIC: COSV64671974;