chr1-94062587-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1PM5BP4_StrongBS1BS2

The NM_000350.3(ABCA4):​c.1927G>A​(p.Val643Met) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,614,030 control chromosomes in the GnomAD database, including 14 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. V643G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 8 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

2
13
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9O:1

Conservation

PhyloP100: 6.16
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 Benign. Variant got -8 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94062586-A-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.010616779).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00464 (707/152244) while in subpopulation AFR AF= 0.0163 (676/41542). AF 95% confidence interval is 0.0153. There are 6 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.1927G>A p.Val643Met missense_variant Exon 13 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.1927G>A p.Val643Met missense_variant Exon 13 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.1927G>A p.Val643Met missense_variant Exon 13 of 50 1 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000649773.1 linkc.1927G>A p.Val643Met missense_variant Exon 13 of 19 ENSP00000496882.1 A0A3B3IRV8

Frequencies

GnomAD3 genomes
AF:
0.00463
AC:
705
AN:
152126
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0162
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00138
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00132
AC:
332
AN:
251106
Hom.:
2
AF XY:
0.00108
AC XY:
147
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.0174
Gnomad AMR exome
AF:
0.000896
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000816
GnomAD4 exome
AF:
0.000506
AC:
739
AN:
1461786
Hom.:
8
Cov.:
37
AF XY:
0.000446
AC XY:
324
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.0169
Gnomad4 AMR exome
AF:
0.00103
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000540
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.00464
AC:
707
AN:
152244
Hom.:
6
Cov.:
32
AF XY:
0.00426
AC XY:
317
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0163
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.000778
Hom.:
2
Bravo
AF:
0.00554
ESP6500AA
AF:
0.0182
AC:
80
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00161
AC:
196
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:9Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2Other:1
Jun 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ABCA4: PM3:Strong, PM2:Supporting, PP3, BS2 -

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

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 30, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 24265693, 25066811, 28044389, 25082885, 25097241, 25910913, 11527935, 22328824, 29925512, 32619608) -

Retinal dystrophy Uncertain:2
Jan 01, 2019
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 02, 2019
Blueprint Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis Pigmentosa, Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
May 13, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Stargardt Disease, Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy Benign:1
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ABCA4-related disorder Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cone-Rod Dystrophy, Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Macular degeneration Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D
MetaRNN
Benign
0.011
T;T
MetaSVM
Uncertain
0.64
D
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.4
N;.
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0030
D;.
Sift4G
Uncertain
0.0050
D;.
Polyphen
0.99
D;.
Vest4
0.87
MVP
0.93
MPC
0.47
ClinPred
0.029
T
GERP RS
4.0
Varity_R
0.58
gMVP
0.85

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

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

Other links and lift over

dbSNP: rs61749417; hg19: chr1-94528143; API