rs1800549

Variant names:

• chr1-94030497-G-A
• rs1800549
• NM_000350.3:c.4283C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-94030497-G-A
• chr1-94030497-G-C
• chr1-94030497-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000350.3(ABCA4):​c.4283C>T​(p.Thr1428Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,614,220 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1428T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (49 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11 O:1
• Conservation: PhyloP100: -0.451
• Publications: 27 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025619566).
• BP6: Variant 1-94030497-G-A is Benign according to our data. Variant chr1-94030497-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99271.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00221 (337/152354) while in subpopulation EAS AF = 0.0528 (273/5174). AF 95% confidence interval is 0.0476. There are 6 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.4283C>T	p.Thr1428Met	missense	Exon 29 of 50	NP_000341.2
	ABCA4	NM_001425324.1		c.4061C>T	p.Thr1354Met	missense	Exon 28 of 49	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.4283C>T	p.Thr1428Met	missense	Exon 29 of 50	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152238 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0532

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00457 AC: 1150 AN: 251468 AF XY: 0.00428

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0553

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00155 AC: 2262 AN: 1461866 Hom.: 49 Cov.: 32 AF XY: 0.00152 AC XY: 1102 AN XY: 727230

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26136

East Asian (EAS) AF: 0.0444 AC: 1762 AN: 39700

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86258

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112004

Other (OTH) AF: 0.00283 AC: 171 AN: 60394

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152354 Hom.: 6 Cov.: 33 AF XY: 0.00264 AC XY: 197 AN XY: 74504

African (AFR) AF: 0.000289 AC: 12 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0528 AC: 273 AN: 5174

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00134 Hom.: 22

Bravo AF: 0.00260

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00412 AC: 500

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	1	1	Retinal dystrophy (2)
-	-	1	ABCA4-related disorder (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	not specified (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	2.0
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.25
Sift	Benign	0.032	D
Sift4G	Benign	0.10	T
Polyphen		0.17	B
Vest4		0.059
MVP		0.88
MPC		0.088
ClinPred		0.0027	T
GERP RS		1.1
Varity_R		0.018
gMVP		0.64
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1800549; hg19: chr1-94496053;