rs1800548

chr1-94077833-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_000350.3(ABCA4):c.1411G>A(p.Glu471Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 1,614,108 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. E471Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00088 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:3 O:1
• Conservation: PhyloP100: 0.741

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]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94077833-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.008672595).
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1411G>A	p.Glu471Lys	missense_variant	11/50	ENST00000370225.4
LOC124904222	XR_007066231.1	n.203-5896C>T		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1	c.1411G>A	p.Glu471Lys	missense_variant	11/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1411G>A	p.Glu471Lys	missense_variant	11/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1411G>A	p.Glu471Lys	missense_variant	11/19

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000831 AC: 209 AN: 251400 Hom.: 0 AF XY: 0.000846 AC XY: 115 AN XY: 135868

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000709 AC: 1037 AN: 1461882 Hom.: 1 Cov.: 31 AF XY: 0.000745 AC XY: 542 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152226 Hom.: 2 Cov.: 32 AF XY: 0.000807 AC XY: 60 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00115

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	Reported in individuals with Stargardt disease sometimes co-occurring with other ABCA4 variants, but it is not always known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Lewis et al., 1999; Rivera et al., 2000; Stone et al., 2003; Fujinami et al., 2013; Sharon et al., 2020); Published functional studies demonstrate no impact on ATP binding and hydrolysis (Sun et al., 2000); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31456290, 11017087, 23953153, 27535533, 9781034, 28446513, 12037008, 10090887, 16546111, 12796258, 27491360, 18977788, 19074458, 19230850, 25087612, 9295268, 9973280, 14971589, 10958763, 11919200) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ABCA4: BP4 -

Stargardt disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Age related macular degeneration 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Oct 09, 2018

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2017

- -

ABCA4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 31, 2023

This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C and NM_000350.3:c.5693G>A. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 15, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 02, 2023

Variant summary: ABCA4 c.1411G>A (p.Glu471Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251400 control chromosomes in GnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00083 vs 0.0014), allowing no conclusion about variant significance. c.1411G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa or Stargardt disease, but the second pathogenic variant and the phase information are not always known (example: Allikmets_1997, Lewis_1999, Hanany_2020, Reinhard_2007, Sharon_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (phase unknown with p.Gly863Ala and p.Asp1532Asn of ABCA4; in cis with c.4919G>A/p.Arg1640Gln of ABCA4), providing supporting evidence for a benign role (Fujinami_2013 and Mena_2021). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Sun_2000). The following publications have been ascertained in the context of this evaluation (PMID: 9295268, 23953153, 31964843, 33841504, 17562343, 10958763, 31456290, 11017087, 11328725). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS: 8, Likely pathognic: 1, Benign: 1) . Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	20
Dann	Benign	0.88
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0027
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.58	N;.
REVEL	Uncertain	0.49
Sift	Benign	0.92	T;.
Sift4G	Benign	0.76	T;.
Polyphen		0.0040	B;.
Vest4		0.80
MVP		0.86
MPC		0.10
ClinPred		0.036	T
GERP RS		4.9
Varity_R		0.23
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800548; hg19: chr1-94543389; COSMIC: COSV64678302;