chr1-93993103-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000350.3(ABCA4):​c.*134G>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 0.00306 in 1,190,572 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 55 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 36 hom. )

Consequence

ABCA4
NM_000350.3 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.13
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 1-93993103-C-T is Benign according to our data. Variant chr1-93993103-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 298219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2146/152148) while in subpopulation AFR AF= 0.0491 (2036/41508). AF 95% confidence interval is 0.0473. There are 55 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 55 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.*134G>A 3_prime_UTR_variant 50/50 ENST00000370225.4 NP_000341.2
ABCA4XM_047416704.1 linkuse as main transcriptc.*134G>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.*134G>A 3_prime_UTR_variant 50/501 NM_000350.3 ENSP00000359245 P1

Frequencies

GnomAD3 genomes
AF:
0.0141
AC:
2145
AN:
152030
Hom.:
56
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0492
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00525
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00909
GnomAD4 exome
AF:
0.00144
AC:
1499
AN:
1038424
Hom.:
36
Cov.:
13
AF XY:
0.00121
AC XY:
643
AN XY:
531216
show subpopulations
Gnomad4 AFR exome
AF:
0.0482
Gnomad4 AMR exome
AF:
0.00256
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000201
Gnomad4 FIN exome
AF:
0.0000211
Gnomad4 NFE exome
AF:
0.000122
Gnomad4 OTH exome
AF:
0.00232
GnomAD4 genome
AF:
0.0141
AC:
2146
AN:
152148
Hom.:
55
Cov.:
32
AF XY:
0.0131
AC XY:
973
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.0491
Gnomad4 AMR
AF:
0.00524
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00900
Alfa
AF:
0.00317
Hom.:
15
Bravo
AF:
0.0163
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJul 05, 2018- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
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- -
ABCA4-related disorder Benign:1
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Cone-Rod Dystrophy, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
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
-0.86
CADD
Benign
0.32
DANN
Benign
0.83

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: rs76201551; hg19: chr1-94458659; API