chr1-94029522-A-G

Variant names:

• chr1-94029522-A-G
• rs61750146
• NM_000350.3:c.4462T>C

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000350.3(ABCA4):​c.4462T>C​(p.Cys1488Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000321351: Functional studies have shown that C1488R results in lowered ATPase activity compared to wild type (Sun et al., 2000)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1488F) has been classified as Likely pathogenic. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 9.16
• Publications: 29 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: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321351: Functional studies have shown that C1488R results in lowered ATPase activity compared to wild type (Sun et al., 2000).; SCV001222273: Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087).; SCV001248244: PS3:Supporting
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94029521-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 99286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 severe early-childhood-onset retinal dystrophy, retinitis pigmentosa, age related macular degeneration 2, retinitis pigmentosa 19, cone-rod dystrophy 3, ABCA4-related retinopathy, Stargardt disease, cone-rod dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-94029522-A-G is Pathogenic according to our data. Variant chr1-94029522-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 99284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4462T>C	p.Cys1488Arg	missense	Exon 30 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.4240T>C	p.Cys1414Arg	missense	Exon 29 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.4462T>C	p.Cys1488Arg	missense	Exon 30 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000820 AC: 2 AN: 243976 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000961 AC: 14 AN: 1457138 Hom.: 0 Cov.: 31 AF XY: 0.00000966 AC XY: 7 AN XY: 724272

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000588 AC: 5 AN: 85084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109700

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000311 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (5)
3	-	-	Retinal dystrophy (3)
2	-	-	Severe early-childhood-onset retinal dystrophy (2)
1	-	-	ABCA4-related disorder (1)
1	-	-	Cone-rod dystrophy (1)
1	-	-	Cone-rod dystrophy 3 (1)
1	-	-	Retinitis pigmentosa 19 (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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.87	P
Vest4		0.94
MVP		0.98
MPC		0.62
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61750146; hg19: chr1-94495078;