1-93992865-T-C

Variant names:

• chr1-93992865-T-C
• rs3747961
• NM_000350.3:c.*372A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):​c.*372A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 335,058 control chromosomes in the GnomAD database, including 975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (668 hom., cov: 32)
  • Exomes 𝑓: 0.047 (307 hom.)
• Consequence: ABCA4 NM_000350.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.662

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-93992865-T-C is Benign according to our data. Variant chr1-93992865-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 298215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.*372A>G		3_prime_UTR_variant	Exon 50 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.*372A>G		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.*372A>G		3_prime_UTR_variant	Exon 50 of 50	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11567 AN: 152118 Hom.: 668 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.0673

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0429

Gnomad OTH AF: 0.0804

GnomAD4 exome AF: 0.0470 AC: 8596 AN: 182822 Hom.: 307 Cov.: 0 AF XY: 0.0485 AC XY: 4703 AN XY: 97060

African (AFR) AF: 0.168 AC: 1006 AN: 5994

American (AMR) AF: 0.0481 AC: 410 AN: 8528

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 189 AN: 4922

East Asian (EAS) AF: 0.0407 AC: 407 AN: 10006

South Asian (SAS) AF: 0.0595 AC: 1678 AN: 28208

European-Finnish (FIN) AF: 0.00785 AC: 67 AN: 8530

Middle Eastern (MID) AF: 0.0919 AC: 66 AN: 718

European-Non Finnish (NFE) AF: 0.0404 AC: 4292 AN: 106118

Other (OTH) AF: 0.0491 AC: 481 AN: 9798

GnomAD4 genome AF: 0.0760 AC: 11570 AN: 152236 Hom.: 668 Cov.: 32 AF XY: 0.0744 AC XY: 5536 AN XY: 74458

African (AFR) AF: 0.163 AC: 6750 AN: 41496

American (AMR) AF: 0.0559 AC: 855 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.0508 AC: 263 AN: 5180

South Asian (SAS) AF: 0.0663 AC: 320 AN: 4828

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0429 AC: 2921 AN: 68024

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0531 Hom.: 560

Bravo AF: 0.0839

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

ABCA4-related disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.8
DANN	Benign	0.73
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

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: rs3747961; hg19: chr1-94458421;