rs1800717

Variant names:

• chr1-93996198-A-G
• rs1800717
• NM_000350.3:c.6730-3T>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.6730-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,608,004 control chromosomes in the GnomAD database, including 7,710 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3492 hom., cov: 33)
  • Exomes 𝑓: 0.048 (4218 hom.)
• Consequence: ABCA4 NM_000350.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002718
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:2
• Conservation: PhyloP100: 0.779
• Publications: 17 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=-0.82).
• BP6: Variant 1-93996198-A-G is Benign according to our data. Variant chr1-93996198-A-G is described in ClinVar as Benign. ClinVar VariationId is 99491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.6730-3T>C		splice_region intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.6508-3T>C		splice_region intron	N/A	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6730-3T>C		splice_region intron	N/A	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21622 AN: 152132 Hom.: 3478 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0652 AC: 16361 AN: 250840 AF XY: 0.0582

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0633

GnomAD4 exome AF: 0.0481 AC: 70066 AN: 1455754 Hom.: 4218 Cov.: 30 AF XY: 0.0474 AC XY: 34334 AN XY: 724640

African (AFR) AF: 0.411 AC: 13601 AN: 33076

American (AMR) AF: 0.0601 AC: 2688 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1825 AN: 26102

East Asian (EAS) AF: 0.0229 AC: 907 AN: 39668

South Asian (SAS) AF: 0.0504 AC: 4344 AN: 86150

European-Finnish (FIN) AF: 0.00681 AC: 361 AN: 52990

Middle Eastern (MID) AF: 0.121 AC: 698 AN: 5750

European-Non Finnish (NFE) AF: 0.0375 AC: 41546 AN: 1107108

Other (OTH) AF: 0.0680 AC: 4096 AN: 60196

GnomAD4 genome AF: 0.142 AC: 21674 AN: 152250 Hom.: 3492 Cov.: 33 AF XY: 0.138 AC XY: 10257 AN XY: 74452

African (AFR) AF: 0.400 AC: 16585 AN: 41500

American (AMR) AF: 0.0847 AC: 1296 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5188

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4822

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0407 AC: 2769 AN: 68020

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.0763 Hom.: 2292

Bravo AF: 0.160

Asia WGS AF: 0.0640 AC: 223 AN: 3478

EpiCase AF: 0.0497

EpiControl AF: 0.0504

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (4)
-	-	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	-0.82
CADD	Benign	4.0
DANN	Benign	0.61
PhyloP100		0.78
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0040
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: rs1800717; hg19: chr1-94461754;