1-93993101-C-T

Variant names:

• chr1-93993101-C-T
• rs55665437
• NM_000350.3:c.*136G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.141

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]

ACMG classification

Our verdict: Benign. The variant received -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: {Uncertain_significance=1, Likely_benign=4, Benign=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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.*136G>A		3_prime_UTR_variant	Exon 50 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.*136G>A		3_prime_UTR_variant	Exon 49 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.*136G>A		3_prime_UTR_variant	Exon 50 of 50	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 152032 Hom.: 4 Cov.: 32

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

African (AFR) AF: 0.000781 AC: 19 AN: 24326

American (AMR) AF: 0.00228 AC: 86 AN: 37772

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 24 AN: 22586

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.0293 AC: 2165 AN: 73926

European-Finnish (FIN) AF: 0.00132 AC: 62 AN: 47024

Middle Eastern (MID) AF: 0.0149 AC: 52 AN: 3492

European-Non Finnish (NFE) AF: 0.00764 AC: 5598 AN: 733158

Other (OTH) AF: 0.00776 AC: 355 AN: 45754

GnomAD4 genome AF: 0.00530 AC: 806 AN: 152150 Hom.: 4 Cov.: 32 AF XY: 0.00540 AC XY: 402 AN XY: 74388

African (AFR) AF: 0.00132 AC: 55 AN: 41520

American (AMR) AF: 0.00222 AC: 34 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0289 AC: 139 AN: 4806

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10590

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00787 AC: 535 AN: 67986

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00711 Hom.: 6

Bravo AF: 0.00442

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ABCA4-related disorder Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

- -

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

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.81
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

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