rs61751396

chr1-94051710-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000350.3(ABCA4):c.2588-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,606,312 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: ABCA4 NM_000350.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002411
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: -0.215

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-94051710-G-C is Benign according to our data. Variant chr1-94051710-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99148.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, not_provided=1, Uncertain_significance=2, Likely_benign=1}. Variant chr1-94051710-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.2588-12C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.2366-12C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.2588-12C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.2366-12C>G		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00219 AC: 549 AN: 250902 Hom.: 3 AF XY: 0.00221 AC XY: 300 AN XY: 135610

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000951

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00226 AC: 3293 AN: 1454000 Hom.: 11 Cov.: 28 AF XY: 0.00221 AC XY: 1602 AN XY: 724014

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00786

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000965

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00279

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74474

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00291

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00167

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCA4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2016

- -

ABCA4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2011

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.1
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.012
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: rs61751396; hg19: chr1-94517266;