rs546550

Variant names:

• chr1-94084999-A-G
• rs546550
• NM_000350.3:c.769-1558T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000350.3(ABCA4):​c.769-1558T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,130 control chromosomes in the GnomAD database, including 5,100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5100 hom., cov: 32)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.301
• Publications: 6 publications found

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]

ABCA4 Gene-Disease associations (from GenCC):

• ABCA4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124904222 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.769-1558T>C		intron_variant	Intron 6 of 49	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1	n.1473A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ABCA4	NM_001425324.1	c.769-1558T>C		intron_variant	Intron 6 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.769-1558T>C		intron_variant	Intron 6 of 49	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.769-1558T>C		intron_variant	Intron 6 of 18			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37432 AN: 152012 Hom.: 5094 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.258

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.246 AC: 37457 AN: 152130 Hom.: 5100 Cov.: 32 AF XY: 0.242 AC XY: 17991 AN XY: 74380

African (AFR) AF: 0.143 AC: 5925 AN: 41506

American (AMR) AF: 0.258 AC: 3949 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3470

East Asian (EAS) AF: 0.213 AC: 1099 AN: 5170

South Asian (SAS) AF: 0.151 AC: 727 AN: 4824

European-Finnish (FIN) AF: 0.253 AC: 2674 AN: 10582

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21431 AN: 67982

Other (OTH) AF: 0.257 AC: 542 AN: 2108

Alfa AF: 0.287 Hom.: 11184

Bravo AF: 0.242

Asia WGS AF: 0.186 AC: 647 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.47
PhyloP100		0.30
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

Other links and lift over

dbSNP: rs546550; hg19: chr1-94550555;