rs4147856

Positions:

• chr1-94008896-T-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.5715-25A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,608,624 control chromosomes in the GnomAD database, including 29,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3146 hom., cov: 30)
  • Exomes 𝑓: 0.19 (26392 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -3.85

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 1-94008896-T-G is Benign according to our data. Variant chr1-94008896-T-G is described in ClinVar as [Benign]. Clinvar id is 99404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94008896-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.5715-25A>C		intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.5493-25A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.5715-25A>C		intron_variant		1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.131-25A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30336 AN: 150944 Hom.: 3131 Cov.: 30

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.190 AC: 47287 AN: 248922 Hom.: 4786 AF XY: 0.184 AC XY: 24852 AN XY: 134800

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.187 AC: 273237 AN: 1457562 Hom.: 26392 Cov.: 33 AF XY: 0.186 AC XY: 134601 AN XY: 725322

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.201 AC: 30403 AN: 151062 Hom.: 3146 Cov.: 30 AF XY: 0.198 AC XY: 14619 AN XY: 73746

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.194

Alfa AF: 0.195 Hom.: 3979

Bravo AF: 0.208

Asia WGS AF: 0.161 AC: 561 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

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

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	-0.83
CADD	Benign	0.0020
DANN	Benign	0.74

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: rs4147856; hg19: chr1-94474452; COSMIC: COSV64672050; COSMIC: COSV64672050;