chr1-94007731-G-A

Variant names:

• chr1-94007731-G-A
• rs28938473
• NM_000350.3:c.5908C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1 PM5 PP3 BP4_Strong BS2

The NM_000350.3(ABCA4):​c.5908C>T​(p.Leu1970Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00479 in 1,613,956 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1970I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (24 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:4 O:1
• Conservation: PhyloP100: 6.77

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94007731-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1392712.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0254018).
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.5908C>T	p.Leu1970Phe	missense_variant	Exon 43 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.5686C>T	p.Leu1896Phe	missense_variant	Exon 42 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.5908C>T	p.Leu1970Phe	missense_variant	Exon 43 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000465352.1	n.324C>T		non_coding_transcript_exon_variant	Exon 4 of 6	5
ABCA4	ENST00000484388.1	n.22C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 538 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00300 AC: 751 AN: 250638 Hom.: 2 AF XY: 0.00308 AC XY: 418 AN XY: 135618

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00492 AC: 7186 AN: 1461696 Hom.: 24 Cov.: 31 AF XY: 0.00474 AC XY: 3443 AN XY: 727136

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00353 AC: 538 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74462

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00454 Hom.: 3

Bravo AF: 0.00388

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00290 AC: 352

EpiCase AF: 0.00496

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	This variant is associated with the following publications: (PMID: 9781034, 25087612, 9295268, 23953153, 9973280, 10958763, 12515255, 22264887, 28118664, 27408750, 28157192, 29925512, 30718709, 33633436) -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ABCA4: PM5:Supporting, PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2025	- -

ABCA4-related disorder Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 27, 2024	The ABCA4 c.5908C>T variant is predicted to result in the amino acid substitution p.Leu1970Phe. This variant has been reported many times in individuals with Stargardt disease, late-onset fundus flavimaculatus, and/or age-related macular degeneration (Lewis et al. 1999. PubMed ID: 9973280; Allikmets et al. 1997. PubMed ID: 9295268; Rozet et al. 1998. PubMed ID: 9781034; Webster et al. 2001. PubMed ID: 11328725; Thiadens et al. 2012. PubMed ID: 22264887; Fujinami et al. 2019. PubMed ID: 29925512). However, in some of these cases a second causative variant in ABCA4 was not detected. Additionally, this variant has been reported in individuals in which there were pathogenic variants in different genes that could explain their inherited retinal dystrophy (Jespersgaard et al. 2019. PubMed ID: 30718709; Zhu et al. 2022. PubMed ID: 35456422). Here, at PreventionGenetics, we have also detected this variant in the absence of a second causative variant, and sometimes these individuals were positive for pathogenic variants in different genes (Internal Data). This variant is documented in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/1-94473287-G-A). Given the conflicting evidence, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2017	The ABCA4 c.5908C>T (p.Leu1970Phe) missense variant has been reported in at least eleven studies in which it is found in at least thirteen individuals with ABCA4-related disorders including in three in a compound heterozygous state and in ten in a heterozygous state (Allikmets et al. 1997; Rozet et al 1998; Lewis et al 1999; Rivera et al 2000; Souied et al 2000; Webster et al 2001; Bernstein et al 2002; Ducroq et al. 2002; Riveiro-Alvarez et al 2009; Thiadens et al. 2012; Schulz et al. 2017). The individuals exhibited a variety of phenotypes. Two of the compound heterozygous individuals were diagnosed with Stargardt disease and one with a related eye disorder, late-onset fundus flavimaculatus. Of the ten heterozygous individuals, six, including one set of three siblings and one pair of siblings, were diagnosed with dominantly inherited age-related macular degeneration. A second variant was not detected in the remaining four heterozygous individuals, two of whom were diagnosed with recessively inherited Stargardt disease, and two with recessively inherited cone or cone-rod dystrophy. The p.Leu1970Phe variant was reported in two of 1608 control chromosomes (Allikmets et al. 1997; Rozet et al 1998; Rivera et al 2000; Riveiro-Alvarez et al 2009) and is reported at a frequency of 0.00596 in the European population of the 1000 Genomes Project. The p.Leu1970Phe variant has also been reported in a homozygous state in three individuals from the Genome Aggregation Database, which may be inconsistent with the clinical significance of this variant. In vitro expression analysis in HEK293T cells found that the p.Leu1970Phe variant is associated with reduced protein expression and ATP-binding, which is suggestive of protein misfolding (Shroyer et al. 2001). The p.Leu1970Phe variant occurs at an amino acid position that is conserved in both the ATP-binding cassette superfamily and ABCA4 mouse ortholog (Rozet et al. 1998). Based on the evidence, the p.Leu1970Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinal dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 30, 2018	- -

Vitreoretinopathy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Stargardt disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1998

- -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Aug 27, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	.;D
REVEL	Pathogenic	0.89
Sift	Benign	0.068	.;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.96
MVP		0.94
MPC		0.48
ClinPred		0.0086	T
GERP RS		5.1
Varity_R		0.61
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs28938473; hg19: chr1-94473287; COSMIC: COSV99058777;