rs886044742

Variant names:

• chr1-94029630-C-A
• rs886044742
• NM_000350.3:c.4354G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000350.3(ABCA4):​c.4354G>T​(p.Glu1452*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1452E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA4 NM_000350.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.8050
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.20
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-94029630-C-A is Pathogenic according to our data. Variant chr1-94029630-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 236114.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
ABCA4	NM_000350.3	c.4354G>T	p.Glu1452*	stop_gained, splice_region_variant	Exon 30 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.4132G>T	p.Glu1378*	stop_gained, splice_region_variant	Exon 29 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.4354G>T	p.Glu1452*	stop_gained, splice_region_variant	Exon 30 of 50	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Jan 01, 2016

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

- -

not provided Pathogenic:1

Feb 19, 2024

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.Glu1452*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Stargardt disease (PMID: 28118664). ClinVar contains an entry for this variant (Variation ID: 236114). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Jan 01, 2010

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		1.2
Vest4		0.93
GERP RS		4.0
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886044742; hg19: chr1-94495186;