1-94018445-C-T

Position:

chr1-94018445-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_000350.3(ABCA4):c.5196+1137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 411,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: -0.407

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]

ABCA4 links:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 1-94018445-C-T is Pathogenic according to our data. Variant chr1-94018445-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94018445-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94018445-C-T is described in Lovd as [Pathogenic]. Variant chr1-94018445-C-T is described in Lovd as [Pathogenic]. Variant chr1-94018445-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.5196+1137G>A		intron_variant		ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.4974+1137G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.5196+1137G>A		intron_variant		1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

AN:

259626

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

147164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000923

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000795

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000118

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000155

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change falls in intron 36 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs778234759, gnomAD 0.01%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662, 25474345, 29925512). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438100). Studies have shown that this variant results in the insertion of an out of frame exon and introduces a premature termination codon (PMID: 23918662). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2023	Published functional studies suggest a damaging effect (alternate splicing products compared to controls and an abnormal protein product) (Braun et al., 2013); This variant is associated with the following publications: (PMID: 25082829, 25363634, 34795310, 34758253, 25346251, 23918662, 28341476, 28041643, 28118664, 29555955, 28224992, 25474345, 29925512, 30718709, 31614660, 32581362, 33851411, 32619608, 32037395, 35119454, 35409265) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -

Retinal dystrophy

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -

Macular dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Cone-rod dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Retinitis pigmentosa 19

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

- -

Stargardt disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.6

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over