1-94029446-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000350.3(ABCA4):​c.4537dupC​(p.Gln1513ProfsTer42) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000219 in 1,549,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1513Q) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 6.68
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 1-94029446-T-TG is Pathogenic according to our data. Variant chr1-94029446-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 99292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.4537dupC p.Gln1513ProfsTer42 frameshift_variant, splice_region_variant Exon 30 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.4315dupC p.Gln1439ProfsTer42 frameshift_variant, splice_region_variant Exon 29 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.4537dupC p.Gln1513ProfsTer42 frameshift_variant, splice_region_variant Exon 30 of 50 1 NM_000350.3 ENSP00000359245.3 P78363

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000222
AC:
31
AN:
1397334
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
18
AN XY:
689166
show subpopulations
Gnomad4 AFR exome
AF:
0.0000315
Gnomad4 AMR exome
AF:
0.0000558
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000554
Gnomad4 SAS exome
AF:
0.0000252
Gnomad4 FIN exome
AF:
0.0000830
Gnomad4 NFE exome
AF:
0.0000148
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152094
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3Other:1
-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Oct 17, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26872967, 11527935, 25097154, 18652558, 22968130, 24938718, 29555955, 28041643, 31872526, 32581362, 32619608, 31429209, 32531858, 34758253, 29925512) -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 11, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1513Profs*42) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: 11527935, 28041643). ClinVar contains an entry for this variant (Variation ID: 99292). For these reasons, this variant has been classified as Pathogenic. -

Severe early-childhood-onset retinal dystrophy Pathogenic:2
-
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 22, 2015
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinitis pigmentosa 19 Pathogenic:2
-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 01, 2016
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 11, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Macular dystrophy Pathogenic:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Cone-rod dystrophy Pathogenic:1
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Cone-rod dystrophy 3 Pathogenic:1
Dec 03, 2018
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The heterozygous p.Gln1513ProfsTer42 variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with cone-rod dystrophy. The p.Gln1513ProfsTer42 variant in ABCA4 has not been previously reported in individuals with cone-rod dystrophy but has been identified in 0.004031% (6/148860) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs281865377). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1513 and leads to a premature termination codon 42 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive cone-rod dystrophy, and this is a loss of function variant. The presence of this variant in combination with a likely pathogenic variant and in an individual with cone-rod dystrophy increases the likelihood that the p.Gln1513ProfsTer42 variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for cone-rod dystrophy in an autosomal recessive manner based on the predicted impact of the variant and the presence of a likely pathogenic variant in trans. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015). -

Retinitis pigmentosa Pathogenic:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281865377; hg19: chr1-94495002; API