chr1-93993101-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000350.3(ABCA4):​c.*136G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00779 in 1,176,140 control chromosomes in the GnomAD database, including 97 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 0.0053 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0082 ( 93 hom. )

Consequence

ABCA4
NM_000350.3 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.141
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 -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 1-93993101-C-T is Benign according to our data. Variant chr1-93993101-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298218.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0053 (806/152150) while in subpopulation SAS AF= 0.0289 (139/4806). AF 95% confidence interval is 0.025. There are 4 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.*136G>A 3_prime_UTR_variant 50/50 ENST00000370225.4 NP_000341.2
ABCA4XM_047416704.1 linkuse as main transcriptc.*136G>A 3_prime_UTR_variant 49/49 XP_047272660.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.*136G>A 3_prime_UTR_variant 50/501 NM_000350.3 ENSP00000359245 P1

Frequencies

GnomAD3 genomes
AF:
0.00530
AC:
806
AN:
152032
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00133
Gnomad AMI
AF:
0.0110
Gnomad AMR
AF:
0.00223
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0285
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.0316
Gnomad NFE
AF:
0.00787
Gnomad OTH
AF:
0.00527
GnomAD4 exome
AF:
0.00817
AC:
8361
AN:
1023990
Hom.:
93
Cov.:
13
AF XY:
0.00916
AC XY:
4799
AN XY:
524056
show subpopulations
Gnomad4 AFR exome
AF:
0.000781
Gnomad4 AMR exome
AF:
0.00228
Gnomad4 ASJ exome
AF:
0.00106
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0293
Gnomad4 FIN exome
AF:
0.00132
Gnomad4 NFE exome
AF:
0.00764
Gnomad4 OTH exome
AF:
0.00776
GnomAD4 genome
AF:
0.00530
AC:
806
AN:
152150
Hom.:
4
Cov.:
32
AF XY:
0.00540
AC XY:
402
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00132
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.0289
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00787
Gnomad4 OTH
AF:
0.00474
Alfa
AF:
0.00727
Hom.:
4
Bravo
AF:
0.00442
Asia WGS
AF:
0.00866
AC:
30
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

ABCA4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Retinitis Pigmentosa, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Stargardt Disease, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Cone-Rod Dystrophy, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Macular degeneration Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
1.5
DANN
Benign
0.81

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: rs55665437; hg19: chr1-94458657; COSMIC: COSV64674150; API