chr1-94078652-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_000350.3(ABCA4):​c.1294G>A​(p.Glu432Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,499,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 26)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

3
5
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.83
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 -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3
BP4
Computational evidence support a benign effect (MetaRNN=0.042657107).
BP6
Variant 1-94078652-C-T is Benign according to our data. Variant chr1-94078652-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.1294G>A p.Glu432Lys missense_variant 10/50 ENST00000370225.4
LOC124904222XR_007066231.1 linkuse as main transcriptn.203-5077C>T intron_variant, non_coding_transcript_variant
ABCA4XM_047416704.1 linkuse as main transcriptc.1294G>A p.Glu432Lys missense_variant 10/49

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.1294G>A p.Glu432Lys missense_variant 10/501 NM_000350.3 P1
ABCA4ENST00000649773.1 linkuse as main transcriptc.1294G>A p.Glu432Lys missense_variant 10/19

Frequencies

GnomAD3 genomes
AF:
0.000109
AC:
15
AN:
137574
Hom.:
0
Cov.:
26
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00353
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
39
AN:
251490
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00212
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000112
AC:
152
AN:
1362088
Hom.:
1
Cov.:
38
AF XY:
0.000117
AC XY:
79
AN XY:
676196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00484
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000743
GnomAD4 genome
AF:
0.000109
AC:
15
AN:
137664
Hom.:
0
Cov.:
26
AF XY:
0.000168
AC XY:
11
AN XY:
65620
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00354
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000624
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 07, 2024- -
Likely benign, no assertion criteria providedliterature onlyDepartment of Ophthalmology and Visual Sciences Kyoto University-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 15, 2020In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed with two other variants in the ABCA4 gene in an individual with Stargardt disease in published literature, but it is not known what combination of the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sung et al., 2019); This variant is associated with the following publications: (PMID: 23424971, 29975949, 33090715, 33301772) -
Severe early-childhood-onset retinal dystrophy Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
0.0019
T
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;.
Eigen
Benign
0.12
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D;T
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.043
T;T
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
1.7
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.1
N;.
REVEL
Pathogenic
0.66
Sift
Benign
0.17
T;.
Sift4G
Benign
0.19
T;.
Polyphen
0.0020
B;.
Vest4
0.75
MVP
0.83
MPC
0.097
ClinPred
0.13
T
GERP RS
4.6
Varity_R
0.24
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs201117452; hg19: chr1-94544208; COSMIC: COSV64671496; API