rs1762114

Variant names:

• chr1-94005519-A-G
• rs1762114
• NM_000350.3:c.6069T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-94005519-A-G
• chr1-94005519-A-C
• chr1-94005519-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.6069T>C​(p.Ile2023Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,613,940 control chromosomes in the GnomAD database, including 681,263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51992 hom., cov: 32)
  • Exomes 𝑓: 0.92 (629271 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: -1.40
• Publications: 32 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
• age related macular degeneration 2

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-94005519-A-G is Benign according to our data. Variant chr1-94005519-A-G is described in ClinVar as Benign. ClinVar VariationId is 136235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.931 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.6069T>C	p.Ile2023Ile	synonymous	Exon 44 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5847T>C	p.Ile1949Ile	synonymous	Exon 43 of 49	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6069T>C	p.Ile2023Ile	synonymous	Exon 44 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.485T>C		non_coding_transcript_exon	Exon 5 of 6
	ABCA4	ENST00000484388.1	TSL:2	n.183T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121545 AN: 152060 Hom.: 51979 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.821

GnomAD2 exomes AF: 0.898 AC: 225737 AN: 251398 AF XY: 0.906

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 0.885

Gnomad FIN exome AF: 0.958

Gnomad NFE exome AF: 0.938

Gnomad OTH exome AF: 0.910

GnomAD4 exome AF: 0.925 AC: 1351492 AN: 1461762 Hom.: 629271 Cov.: 48 AF XY: 0.925 AC XY: 672778 AN XY: 727188

African (AFR) AF: 0.437 AC: 14618 AN: 33478

American (AMR) AF: 0.932 AC: 41683 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 23140 AN: 26132

East Asian (EAS) AF: 0.908 AC: 36026 AN: 39698

South Asian (SAS) AF: 0.916 AC: 79045 AN: 86256

European-Finnish (FIN) AF: 0.958 AC: 51159 AN: 53416

Middle Eastern (MID) AF: 0.861 AC: 4966 AN: 5768

European-Non Finnish (NFE) AF: 0.941 AC: 1046627 AN: 1111896

Other (OTH) AF: 0.898 AC: 54228 AN: 60394

GnomAD4 genome AF: 0.799 AC: 121610 AN: 152178 Hom.: 51992 Cov.: 32 AF XY: 0.803 AC XY: 59774 AN XY: 74414

African (AFR) AF: 0.460 AC: 19060 AN: 41448

American (AMR) AF: 0.898 AC: 13745 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 3120 AN: 3470

East Asian (EAS) AF: 0.888 AC: 4592 AN: 5174

South Asian (SAS) AF: 0.915 AC: 4417 AN: 4826

European-Finnish (FIN) AF: 0.963 AC: 10217 AN: 10614

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63772 AN: 68026

Other (OTH) AF: 0.821 AC: 1735 AN: 2114

Alfa AF: 0.903 Hom.: 209510

Bravo AF: 0.778

Asia WGS AF: 0.859 AC: 2987 AN: 3478

EpiCase AF: 0.930

EpiControl AF: 0.933

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (4)
-	-	1	ABCA4-related disorder (1)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 19 (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.056
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=78/22	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: rs1762114; hg19: chr1-94471075; COSMIC: COSV64671108;