rs61748550

Positions:

chr1-94079339-G-A

Variant summary

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

The NM_000350.3(ABCA4):c.1222C>T(p.Arg408Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 0.129

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:

LOC124904222 (HGNC:):

LOC124904222 links:

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 1-94079339-G-A is Pathogenic according to our data. Variant chr1-94079339-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 99035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCA4	NM_000350.3 linkuse as main transcript	c.1222C>T	p.Arg408Ter	stop_gained	9/50	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-4390G>A		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1 linkuse as main transcript	c.1222C>T	p.Arg408Ter	stop_gained	9/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1222C>T	p.Arg408Ter	stop_gained	9/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1222C>T	p.Arg408Ter	stop_gained	9/19			ENSP00000496882

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251456

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000406

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	Nonsense 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: 23953153, 25525159, 28947085, 30771335, 16103129, 23755871, 14709597, 11328725, 23891399, 30060493, 33369172, 33301772, 32619608, 35657619, 28118664, 35119454, 11846518) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg408*) 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 present in population databases (rs61748550, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Stargardt disease or retinitis pigmentosa (PMID: 16103129, 23755871). 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: 99035). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2016

- -

Stargardt disease 3

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

- -

Retinitis pigmentosa 19

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The heterozygous p.Arg408Ter variant in ABCA4 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390), in one individual with retinal dystrophy. This individual also carried another pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390); however, the phase of these variants is unknown at this time. The p.Arg408Ter variant in ABCA4 has been previously reported in 13 unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518) and segregated with disease in 2 affected relatives from one family (PMID: 16103129), but has been identified in 0.005% (1/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61748550). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 13 affected individuals (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518), 7 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 23755871, ClinVar Variation ID: 99224, 99283; PMID: 16103129, ClinVar Variation ID: 99084; PMID: 32619608, ClinVar Variation ID: 1065650; PMID: 33301772, ClinVar Variation ID: 99208; PMID: 33369172, ClinVar Variation ID: 854791; PMID: 30771335, ClinVar Variation ID: 7879), one was a compound heterozygote who carried a likely pathogenic variant with unknown phase (PMID: 11846518, ClinVar Variation ID: 99307), and 4 were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 32619608, ClinVar Variation ID: 7888, 99265; PMID: 33301772; PMID: 30060493, ClinVar Variation ID: 866940), which increases the likelihood that the p.Arg408Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 99035) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 408, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong (Richards 2015). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 11, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 28, 2023

Variant summary: ABCA4 c.1222C>T (p.Arg408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. c.1222C>T has been reported in the literature in multiple individuals affected with Stargardt disease (e.g. Riveiro-Alvarez_2013) or other ABCA4-related retinopathy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23755871). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.16

MutationTaster

Benign

1.0

A;A

Vest4

0.90

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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