1-94005519-A-G

Variant names:

• chr1-94005519-A-G
• rs1762114
• NM_000350.3:c.6069T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.6069T>C​(p.Ile2023Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,613,940 control chromosomes in the GnomAD database, including 681,263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51992 hom., cov: 32)
  • Exomes 𝑓: 0.92 (629271 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: -1.40
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• ABCA4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-94005519-A-G is Benign according to our data. Variant chr1-94005519-A-G is described in ClinVar as Benign. ClinVar VariationId is 136235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.6069T>C	p.Ile2023Ile	synonymous	Exon 44 of 50	NP_000341.2
	ABCA4	NM_001425324.1		c.5847T>C	p.Ile1949Ile	synonymous	Exon 43 of 49	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6069T>C	p.Ile2023Ile	synonymous	Exon 44 of 50	ENSP00000359245.3
	ABCA4	ENST00000465352.1	TSL:5	n.485T>C		non_coding_transcript_exon	Exon 5 of 6
	ABCA4	ENST00000484388.1	TSL:2	n.183T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121545 AN: 152060 Hom.: 51979 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.821

GnomAD2 exomes AF: 0.898 AC: 225737 AN: 251398 AF XY: 0.906

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 0.885

Gnomad FIN exome AF: 0.958

Gnomad NFE exome AF: 0.938

Gnomad OTH exome AF: 0.910

GnomAD4 exome AF: 0.925 AC: 1351492 AN: 1461762 Hom.: 629271 Cov.: 48 AF XY: 0.925 AC XY: 672778 AN XY: 727188

African (AFR) AF: 0.437 AC: 14618 AN: 33478

American (AMR) AF: 0.932 AC: 41683 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 23140 AN: 26132

East Asian (EAS) AF: 0.908 AC: 36026 AN: 39698

South Asian (SAS) AF: 0.916 AC: 79045 AN: 86256

European-Finnish (FIN) AF: 0.958 AC: 51159 AN: 53416

Middle Eastern (MID) AF: 0.861 AC: 4966 AN: 5768

European-Non Finnish (NFE) AF: 0.941 AC: 1046627 AN: 1111896

Other (OTH) AF: 0.898 AC: 54228 AN: 60394

GnomAD4 genome AF: 0.799 AC: 121610 AN: 152178 Hom.: 51992 Cov.: 32 AF XY: 0.803 AC XY: 59774 AN XY: 74414

African (AFR) AF: 0.460 AC: 19060 AN: 41448

American (AMR) AF: 0.898 AC: 13745 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 3120 AN: 3470

East Asian (EAS) AF: 0.888 AC: 4592 AN: 5174

South Asian (SAS) AF: 0.915 AC: 4417 AN: 4826

European-Finnish (FIN) AF: 0.963 AC: 10217 AN: 10614

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63772 AN: 68026

Other (OTH) AF: 0.821 AC: 1735 AN: 2114

Alfa AF: 0.903 Hom.: 209510

Bravo AF: 0.778

Asia WGS AF: 0.859 AC: 2987 AN: 3478

EpiCase AF: 0.930

EpiControl AF: 0.933

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Nov 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stargardt Disease, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Age related macular degeneration 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4-related disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Severe early-childhood-onset retinal dystrophy Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-Rod Dystrophy, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa 19 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-rod dystrophy 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.056
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=78/22	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1762114; hg19: chr1-94471075; COSMIC: COSV64671108;