rs1801574

Variant names:

• chr1-94010832-C-G
• rs1801574
• NM_000350.3:c.5682G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-94010832-C-G
• chr1-94010832-C-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.5682G>C​(p.Leu1894Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,792 control chromosomes in the GnomAD database, including 46,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1894L) has been classified as Benign. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.23 (4307 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42197 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 0.299
• Publications: 30 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

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-94010832-C-G is Benign according to our data. Variant chr1-94010832-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.299 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 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.5682G>C	p.Leu1894Leu	synonymous	Exon 40 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5460G>C	p.Leu1820Leu	synonymous	Exon 39 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.5682G>C	p.Leu1894Leu	synonymous	Exon 40 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.98G>C		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35536 AN: 151902 Hom.: 4296 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.216 AC: 54210 AN: 251178 AF XY: 0.214

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.237 AC: 346195 AN: 1461772 Hom.: 42197 Cov.: 40 AF XY: 0.234 AC XY: 170450 AN XY: 727174

African (AFR) AF: 0.258 AC: 8623 AN: 33478

American (AMR) AF: 0.182 AC: 8154 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6190 AN: 26136

East Asian (EAS) AF: 0.136 AC: 5382 AN: 39700

South Asian (SAS) AF: 0.152 AC: 13096 AN: 86256

European-Finnish (FIN) AF: 0.217 AC: 11601 AN: 53410

Middle Eastern (MID) AF: 0.218 AC: 1255 AN: 5768

European-Non Finnish (NFE) AF: 0.250 AC: 278409 AN: 1111916

Other (OTH) AF: 0.223 AC: 13485 AN: 60390

GnomAD4 genome AF: 0.234 AC: 35595 AN: 152020 Hom.: 4307 Cov.: 32 AF XY: 0.229 AC XY: 16984 AN XY: 74304

African (AFR) AF: 0.250 AC: 10354 AN: 41444

American (AMR) AF: 0.192 AC: 2935 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 852 AN: 3470

East Asian (EAS) AF: 0.130 AC: 670 AN: 5142

South Asian (SAS) AF: 0.145 AC: 702 AN: 4828

European-Finnish (FIN) AF: 0.213 AC: 2252 AN: 10576

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.252 AC: 17131 AN: 67976

Other (OTH) AF: 0.220 AC: 463 AN: 2106

Alfa AF: 0.242 Hom.: 3457

Bravo AF: 0.233

Asia WGS AF: 0.152 AC: 531 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.250

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.49
CADD	Benign	2.7
DANN	Benign	0.73
PhyloP100		0.30
Mutation Taster		=97/3	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: rs1801574; hg19: chr1-94476388; COSMIC: COSV64672013; COSMIC: COSV64672013;