1-94111412-T-C

Position:

• chr1-94111412-T-C

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.302+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,611,446 control chromosomes in the GnomAD database, including 204,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18790 hom., cov: 33)
  • Exomes 𝑓: 0.50 (185330 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -2.79

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=-0.93).
• BP6: Variant 1-94111412-T-C is Benign according to our data. Variant chr1-94111412-T-C is described in ClinVar as [Benign]. Clinvar id is 99189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94111412-T-C is described in Lovd as [Benign]. Variant chr1-94111412-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.302+26A>G		intron_variant		ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.302+26A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.302+26A>G		intron_variant		1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.302+26A>G		intron_variant				ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74938 AN: 152034 Hom.: 18759 Cov.: 33

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.481

GnomAD3 exomes AF: 0.520 AC: 129054 AN: 248258 Hom.: 34167 AF XY: 0.518 AC XY: 69390 AN XY: 134072

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.613

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.579

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.502 AC: 732032 AN: 1459294 Hom.: 185330 Cov.: 43 AF XY: 0.503 AC XY: 364911 AN XY: 725820

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.577

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.491

Gnomad4 OTH exome AF: 0.494

GnomAD4 genome AF: 0.493 AC: 75023 AN: 152152 Hom.: 18790 Cov.: 33 AF XY: 0.497 AC XY: 36967 AN XY: 74364

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.417

Gnomad4 EAS AF: 0.657

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.482

Alfa AF: 0.480 Hom.: 24251

Bravo AF: 0.495

Asia WGS AF: 0.606 AC: 2108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Age related macular degeneration 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Retinitis pigmentosa 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cone-rod dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.027
DANN	Benign	0.18

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: rs2297634; hg19: chr1-94576968; COSMIC: COSV64672458;