NM_000350.3:c.6249C>T

Variant names:

• chr1-94001891-G-A
• rs1801359
• NM_000350.3:c.6249C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.6249C>T​(p.Ile2083Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,614,070 control chromosomes in the GnomAD database, including 6,526 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. I2083I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (2077 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4449 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -1.43
• Publications: 19 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-94001891-G-A is Benign according to our data. Variant chr1-94001891-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• 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.6249C>T	p.Ile2083Ile	synonymous	Exon 45 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.6027C>T	p.Ile2009Ile	synonymous	Exon 44 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.6249C>T	p.Ile2083Ile	synonymous	Exon 45 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.665C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19385 AN: 152094 Hom.: 2080 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: 0.0583

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.0767 AC: 19277 AN: 251396 AF XY: 0.0727

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0615

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0602

Gnomad OTH exome AF: 0.0793

GnomAD4 exome AF: 0.0668 AC: 97599 AN: 1461858 Hom.: 4449 Cov.: 32 AF XY: 0.0667 AC XY: 48512 AN XY: 727224

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

American (AMR) AF: 0.0552 AC: 2469 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2875 AN: 26136

East Asian (EAS) AF: 0.0507 AC: 2014 AN: 39700

South Asian (SAS) AF: 0.0710 AC: 6124 AN: 86250

European-Finnish (FIN) AF: 0.0368 AC: 1966 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0594 AC: 66043 AN: 1111992

Other (OTH) AF: 0.0845 AC: 5102 AN: 60392

GnomAD4 genome AF: 0.127 AC: 19404 AN: 152212 Hom.: 2077 Cov.: 33 AF XY: 0.125 AC XY: 9287 AN XY: 74422

African (AFR) AF: 0.293 AC: 12149 AN: 41490

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

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

East Asian (EAS) AF: 0.0581 AC: 301 AN: 5184

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4824

European-Finnish (FIN) AF: 0.0334 AC: 355 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0621 AC: 4224 AN: 68004

Other (OTH) AF: 0.123 AC: 259 AN: 2112

Alfa AF: 0.0905 Hom.: 1560

Bravo AF: 0.139

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.0692

EpiControl AF: 0.0674

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	1	ABCA4-related disorder (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinal dystrophy (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	-0.36
CADD	Benign	0.18
DANN	Benign	0.84
PhyloP100		-1.4
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801359; hg19: chr1-94467447; COSMIC: COSV64673594; COSMIC: COSV64673594;