rs2275029

Variant names:

• chr1-94008289-T-C
• rs2275029
• NM_000350.3:c.5844A>G
• ABCA4 p.Pro1948Pro

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.5844A>G​(p.Pro1948Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,611,868 control chromosomes in the GnomAD database, including 27,055 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. P1948P) has been classified as Uncertain significance. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.19 (2911 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24144 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.193
• Publications: 26 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-0.58).
• BP6: Variant 1-94008289-T-C is Benign according to our data. Variant chr1-94008289-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.193 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 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.5844A>G	p.Pro1948Pro	synonymous	Exon 42 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5622A>G	p.Pro1874Pro	synonymous	Exon 41 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.5844A>G	p.Pro1948Pro	synonymous	Exon 42 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.260A>G		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29303 AN: 151902 Hom.: 2897 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.173 AC: 43438 AN: 251288 AF XY: 0.170

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.179 AC: 261337 AN: 1459848 Hom.: 24144 Cov.: 33 AF XY: 0.178 AC XY: 128988 AN XY: 726322

African (AFR) AF: 0.247 AC: 8269 AN: 33450

American (AMR) AF: 0.159 AC: 7125 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5336 AN: 26122

East Asian (EAS) AF: 0.136 AC: 5393 AN: 39688

South Asian (SAS) AF: 0.133 AC: 11426 AN: 86204

European-Finnish (FIN) AF: 0.176 AC: 9417 AN: 53396

Middle Eastern (MID) AF: 0.172 AC: 992 AN: 5764

European-Non Finnish (NFE) AF: 0.183 AC: 202726 AN: 1110196

Other (OTH) AF: 0.177 AC: 10653 AN: 60316

GnomAD4 genome AF: 0.193 AC: 29369 AN: 152020 Hom.: 2911 Cov.: 32 AF XY: 0.190 AC XY: 14129 AN XY: 74320

African (AFR) AF: 0.238 AC: 9846 AN: 41452

American (AMR) AF: 0.165 AC: 2524 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3468

East Asian (EAS) AF: 0.131 AC: 673 AN: 5148

South Asian (SAS) AF: 0.129 AC: 620 AN: 4812

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10576

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12594 AN: 67962

Other (OTH) AF: 0.185 AC: 392 AN: 2114

Alfa AF: 0.163 Hom.: 6065

Bravo AF: 0.195

Asia WGS AF: 0.158 AC: 550 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.182

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (4)
-	-	1	ABCA4-related disorder (1)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 19 (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.1
DANN	Benign	0.70
PhyloP100		-0.19
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2275029;

hg19: chr1-94473845;

COSMIC: COSV64672034;

COSMIC: COSV64672034;