rs56197337

chr1-94060488-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):c.2160+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,560,890 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (258 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1817 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.238

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-94060488-A-G is Benign according to our data. Variant chr1-94060488-A-G is described in ClinVar as [Benign]. Clinvar id is 255917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.2160+49T>C		intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.2160+49T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.2160+49T>C		intron_variant		1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.2160+49T>C		intron_variant
ABCA4	ENST00000472033.1	n.280+49T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8230 AN: 152176 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0554

GnomAD3 exomes AF: 0.0499 AC: 12426 AN: 249258 Hom.: 333 AF XY: 0.0492 AC XY: 6637 AN XY: 134804

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.0719

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0404

Gnomad SAS exome AF: 0.0582

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0442

GnomAD4 exome AF: 0.0490 AC: 69055 AN: 1408596 Hom.: 1817 Cov.: 26 AF XY: 0.0487 AC XY: 34257 AN XY: 704014

Gnomad4 AFR exome AF: 0.0720

Gnomad4 AMR exome AF: 0.0711

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.0427

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.0440

Gnomad4 NFE exome AF: 0.0480

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.0543 AC: 8266 AN: 152294 Hom.: 258 Cov.: 32 AF XY: 0.0545 AC XY: 4056 AN XY: 74486

Gnomad4 AFR AF: 0.0687

Gnomad4 AMR AF: 0.0751

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.0376

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0473 Hom.: 37

Bravo AF: 0.0574

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	6.0
Dann	Benign	0.68

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

Other links and lift over

dbSNP: rs56197337; hg19: chr1-94526044;