rs17110761

Variant names:

• chr1-94001851-C-T
• rs17110761
• NM_000350.3:c.6282+7G>A

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.6282+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,614,088 control chromosomes in the GnomAD database, including 6,526 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2073 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4453 hom.)
• Consequence: ABCA4 NM_000350.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004080
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.0610
• Publications: 18 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-94001851-C-T is Benign according to our data. Variant chr1-94001851-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 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.6282+7G>A		splice_region intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.6060+7G>A		splice_region 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.6282+7G>A		splice_region intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000465352.1	TSL:5	n.705G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19386 AN: 152132 Hom.: 2075 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.0582

Gnomad SAS AF: 0.0705

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.0766 AC: 19243 AN: 251212 AF XY: 0.0727

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0616

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0668 AC: 97609 AN: 1461836 Hom.: 4453 Cov.: 32 AF XY: 0.0667 AC XY: 48520 AN XY: 727214

African (AFR) AF: 0.307 AC: 10284 AN: 33478

American (AMR) AF: 0.0553 AC: 2474 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2875 AN: 26134

East Asian (EAS) AF: 0.0508 AC: 2017 AN: 39700

South Asian (SAS) AF: 0.0710 AC: 6127 AN: 86254

European-Finnish (FIN) AF: 0.0368 AC: 1966 AN: 53406

Middle Eastern (MID) AF: 0.125 AC: 722 AN: 5768

European-Non Finnish (NFE) AF: 0.0594 AC: 66038 AN: 1111976

Other (OTH) AF: 0.0845 AC: 5106 AN: 60396

GnomAD4 genome AF: 0.127 AC: 19407 AN: 152252 Hom.: 2073 Cov.: 33 AF XY: 0.125 AC XY: 9287 AN XY: 74448

African (AFR) AF: 0.293 AC: 12147 AN: 41508

American (AMR) AF: 0.0785 AC: 1201 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.0579 AC: 300 AN: 5178

South Asian (SAS) AF: 0.0692 AC: 334 AN: 4830

European-Finnish (FIN) AF: 0.0334 AC: 355 AN: 10616

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4228 AN: 68026

Other (OTH) AF: 0.123 AC: 260 AN: 2116

Alfa AF: 0.0976 Hom.: 2029

Bravo AF: 0.139

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.0693

EpiControl AF: 0.0673

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	3	not specified (3)
-	-	1	ABCA4-related disorder (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.37
DANN	Benign	0.73
PhyloP100		-0.061
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.036
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: rs17110761; hg19: chr1-94467407;