NM_000350.3:c.1411G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_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

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:4O: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]

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ACMG classification

Classification made for transcript

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 GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.1411G>A p.Glu471Lys missense_variant Exon 11 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.1411G>A p.Glu471Lys missense_variant Exon 11 of 49 NP_001412253.1
LOC124904222XR_007066231.1 linkn.203-5896C>T intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.1411G>A p.Glu471Lys missense_variant Exon 11 of 50 1 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000649773.1 linkc.1411G>A p.Glu471Lys missense_variant Exon 11 of 19 ENSP00000496882.1 A0A3B3IRV8

Frequencies

GnomAD3 genomes
AF:
0.000880
AC:
134
AN:
152226
Hom.:
2
Cov.:
32
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.:
0
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.:
1
Cov.:
31
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.:
2
Cov.:
32
AF XY:
0.000807
AC XY:
60
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.:
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:1Uncertain:7Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2Other:1
Feb 17, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 17, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate no impact on ATP binding and hydrolysis (PMID: 11017087); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 9295268, 11919200, 10958763, 14971589, 9973280, 18977788, 27491360, 19230850, 19074458, 12796258, 16546111, 10090887, 12037008, 28446513, 9781034, 23953153, 35120629, 31456290, 31964843, 34321860, 11017087) -

Sep 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ABCA4: BP4 -

Retinal dystrophy Uncertain:1Benign:1
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 15, 2019
Blueprint Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Stargardt disease Pathogenic:1
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Age related macular degeneration 2 Uncertain:1
Oct 09, 2018
Centogene AG - the Rare Disease Company
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Aug 28, 2017
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy Uncertain:1
Jan 31, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not specified Benign:1
Jun 02, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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;.
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800548; hg19: chr1-94543389; COSMIC: COSV64678302; API