chr1-94005598-C-T

Variant names:

• chr1-94005598-C-T
• rs4147863
• NM_000350.3:c.6006-16G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):​c.6006-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,610,232 control chromosomes in the GnomAD database, including 24,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2111 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22615 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:2
• Conservation: PhyloP100: -1.53
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-94005598-C-T is Benign according to our data. Variant chr1-94005598-C-T is described in ClinVar as Benign. ClinVar VariationId is 99426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 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.6006-16G>A		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.5784-16G>A		intron	N/A	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6006-16G>A		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000465352.1	TSL:5	n.422-16G>A		intron	N/A
	ABCA4	ENST00000484388.1	TSL:2	n.120-16G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25169 AN: 151916 Hom.: 2107 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.157 AC: 39376 AN: 250816 AF XY: 0.158

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.173 AC: 251558 AN: 1458196 Hom.: 22615 Cov.: 33 AF XY: 0.172 AC XY: 124563 AN XY: 725516

African (AFR) AF: 0.161 AC: 5385 AN: 33398

American (AMR) AF: 0.100 AC: 4477 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5193 AN: 26102

East Asian (EAS) AF: 0.135 AC: 5371 AN: 39680

South Asian (SAS) AF: 0.131 AC: 11308 AN: 86188

European-Finnish (FIN) AF: 0.175 AC: 9321 AN: 53278

Middle Eastern (MID) AF: 0.142 AC: 821 AN: 5764

European-Non Finnish (NFE) AF: 0.180 AC: 199696 AN: 1108794

Other (OTH) AF: 0.166 AC: 9986 AN: 60286

GnomAD4 genome AF: 0.166 AC: 25203 AN: 152036 Hom.: 2111 Cov.: 32 AF XY: 0.163 AC XY: 12136 AN XY: 74300

African (AFR) AF: 0.156 AC: 6484 AN: 41456

American (AMR) AF: 0.128 AC: 1958 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3470

East Asian (EAS) AF: 0.130 AC: 675 AN: 5174

South Asian (SAS) AF: 0.128 AC: 615 AN: 4822

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10550

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12450 AN: 67964

Other (OTH) AF: 0.160 AC: 337 AN: 2110

Alfa AF: 0.170 Hom.: 4013

Bravo AF: 0.162

Asia WGS AF: 0.133 AC: 462 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 23, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 10, 2012

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.

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

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

not provided Benign:2 Other:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

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

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.5
DANN	Benign	0.59
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs4147863; hg19: chr1-94471154; COSMIC: COSV64672003;