rs1800548

Positions:

chr1-94077833-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_StrongBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:3O:1

Conservation

PhyloP100: 0.741

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a disulfide_bond (size 149) in uniprot entity ABCA4_HUMAN there are 76 pathogenic changes around while only 4 benign (95%) in NM_000350.3

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 GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCA4	NM_000350.3 linkuse as main transcript	c.1411G>A	p.Glu471Lys	missense_variant	11/50	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-5896C>T		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1 linkuse as main transcript	c.1411G>A	p.Glu471Lys	missense_variant	11/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1411G>A	p.Glu471Lys	missense_variant	11/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1411G>A	p.Glu471Lys	missense_variant	11/19			ENSP00000496882

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152226

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000846

AC XY:

115

AN XY:

135868

show subpopulations

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.:

Cov.:

AF XY:

0.000745

AC XY:

542

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74372

show subpopulations

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.:

Bravo

AF:

0.000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00115

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
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

- -

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. -

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. -

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

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.0027

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.29

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

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

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