rs1800699

Positions:

• chr1-93997840-G-A
• chr1-93997840-G-T

Variant summary

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

The NM_000350.3(ABCA4):​c.6729+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,726 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (52 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.981

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=-0.83).
• BP6: Variant 1-93997840-G-A is Benign according to our data. Variant chr1-93997840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-93997840-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00972 (1479/152186) while in subpopulation AFR AF= 0.0265 (1099/41522). AF 95% confidence interval is 0.0252. There are 12 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6729+21C>T		intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.6507+21C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6729+21C>T		intron_variant		1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1476 AN: 152068 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0117

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00596 AC: 1494 AN: 250500 Hom.: 12 AF XY: 0.00616 AC XY: 835 AN XY: 135478

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00348 AC: 5084 AN: 1461540 Hom.: 52 Cov.: 31 AF XY: 0.00380 AC XY: 2761 AN XY: 727054

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0232

Gnomad4 EAS exome AF: 0.00297

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00576

GnomAD4 genome AF: 0.00972 AC: 1479 AN: 152186 Hom.: 12 Cov.: 32 AF XY: 0.00961 AC XY: 715 AN XY: 74410

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0117

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00821 Hom.: 2

Bravo AF: 0.0106

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely 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	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Likely 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	-0.83
CADD	Benign	0.39
DANN	Benign	0.45

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: rs1800699; hg19: chr1-94463396;