rs6666559

Variant names:

• chr1-93996081-C-G
• rs6666559
• NM_000350.3:c.6816+28G>C

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.6816+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,605,520 control chromosomes in the GnomAD database, including 7,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.14 (3448 hom., cov: 32)
  • Exomes 𝑓: 0.048 (4197 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.268
• Publications: 5 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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
• age related macular degeneration 2

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for ABCA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-93996081-C-G is Benign according to our data. Variant chr1-93996081-C-G is described in ClinVar as Benign. ClinVar VariationId is 255927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.6816+28G>C		intron	N/A	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.6594+28G>C		intron	N/A	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6816+28G>C		intron	N/A	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21538 AN: 152042 Hom.: 3441 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0652 AC: 16307 AN: 250004 AF XY: 0.0582

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.00590

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0484 AC: 70375 AN: 1453360 Hom.: 4197 Cov.: 30 AF XY: 0.0476 AC XY: 34452 AN XY: 723506

African (AFR) AF: 0.410 AC: 13610 AN: 33174

American (AMR) AF: 0.0601 AC: 2686 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0702 AC: 1832 AN: 26086

East Asian (EAS) AF: 0.0229 AC: 909 AN: 39640

South Asian (SAS) AF: 0.0504 AC: 4336 AN: 86068

European-Finnish (FIN) AF: 0.00686 AC: 361 AN: 52616

Middle Eastern (MID) AF: 0.120 AC: 678 AN: 5658

European-Non Finnish (NFE) AF: 0.0379 AC: 41855 AN: 1105274

Other (OTH) AF: 0.0683 AC: 4108 AN: 60154

GnomAD4 genome AF: 0.142 AC: 21579 AN: 152160 Hom.: 3448 Cov.: 32 AF XY: 0.137 AC XY: 10205 AN XY: 74404

African (AFR) AF: 0.398 AC: 16493 AN: 41446

American (AMR) AF: 0.0843 AC: 1289 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5176

South Asian (SAS) AF: 0.0530 AC: 256 AN: 4826

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10614

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2775 AN: 68024

Other (OTH) AF: 0.124 AC: 261 AN: 2108

Alfa AF: 0.0896 Hom.: 290

Bravo AF: 0.160

Asia WGS AF: 0.0630 AC: 220 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.39
PhyloP100		0.27
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6666559;

hg19: chr1-94461637;