rs76157638

Variant names:

• chr1-94051698-C-G
• rs76157638
• NM_000350.3:c.2588G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-94051698-C-G
• chr1-94051698-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM1 PP2 PP3 PP5_Very_Strong BS1_Supporting

The NM_000350.3(ABCA4):​c.2588G>C​(p.Gly863Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00706 in 1,612,312 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002556399: Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID:11919200, 23144455, 11017087)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G863R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (42 hom.)
• Consequence: ABCA4 NM_000350.3 missense, splice_region
• Scores: Splicing: ADA: 0.9878
• Clinical Significance: Pathogenic reviewed by expert panel P:42 U:3 O:2
• Conservation: PhyloP100: 7.04
• Publications: 161 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002556399: Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087).; SCV002769539: "This variant has moderate functional evidence supporting abnormal protein function. This variant leads to reduced protein expression, ATP-binding affinity, and ATP hydrolysis in in vitro studies (PMID: 11017087, 11919200)."; SCV000538010: "In vitro studies showed that the function of this variant is highly attenuated (Biswas-Fiss et al. 2012)."; SCV000321344: Published functional studies demonstrate that G863A has minimal effect on ATP hydrolysis, but significantly reduces interaction of the nucleotide binding domain 1 of the ABCA4 protein with 11-cis-retinal (Biswas-Fiss et al., 2012); SCV001211627: Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087).; SCV000742856: Functional analysis demonstrated that the p.G863A alteration significantly decreased the rates of nucleotide hydrolysis as well as the binding affinities of the protein (Suárez, 2002); SCV000711736: Both of these variants had impaired protein activity in in vitro studies (Maugeri 1999, Sun 2000, Suarez 2002).; SCV002572288: "Several publications report experimental evidence evaluating an impact on protein function and have found that both Gly863del and Gly863Ala reduce ATPase activity and that Glu863Ala severely impairs interaction with 11-cis-retinal (e.g. Sun_2000, Suarez_2002, Biswas-Fiss_2012)."; SCV004113554: Functional studies demonstrated that this variant results in a decrease of both basal and retinal-stimulated ATPase activity (Sun et al. 2000. PubMed ID: 11017087).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-94051698-C-G is Pathogenic according to our data. Variant chr1-94051698-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7879.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00735 (10730/1459996) while in subpopulation NFE AF = 0.00896 (9952/1110312). AF 95% confidence interval is 0.00882. There are 42 homozygotes in GnomAdExome4. There are 5184 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2588G>C	p.Gly863Ala	missense splice_region	Exon 17 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.2366G>C	p.Gly789Ala	missense splice_region	Exon 16 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.2588G>C	p.Gly863Ala	missense splice_region	Exon 17 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.2366G>C	p.Gly789Ala	missense splice_region	Exon 16 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 645 AN: 152198 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00436 AC: 1096 AN: 251244 AF XY: 0.00467

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00735 AC: 10730 AN: 1459996 Hom.: 42 Cov.: 30 AF XY: 0.00714 AC XY: 5184 AN XY: 726478

African (AFR) AF: 0.00117 AC: 39 AN: 33434

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00193 AC: 166 AN: 86202

European-Finnish (FIN) AF: 0.00182 AC: 97 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00896 AC: 9952 AN: 1110312

Other (OTH) AF: 0.00623 AC: 376 AN: 60338

GnomAD4 genome AF: 0.00423 AC: 645 AN: 152316 Hom.: 4 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74480

African (AFR) AF: 0.00147 AC: 61 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00781 AC: 531 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00686 Hom.: 3

Bravo AF: 0.00394

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00497 AC: 603

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00782

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	not provided (12)
8	-	-	Severe early-childhood-onset retinal dystrophy (8)
3	1	-	Retinal dystrophy (4)
3	-	-	ABCA4-related disorder (3)
3	-	-	Retinitis pigmentosa (3)
3	-	-	Stargardt disease (3)
1	1	-	Age related macular degeneration 2 (2)
2	-	-	Cone-rod dystrophy 3 (2)
1	-	-	ABCA4-related retinopathy (1)
1	-	-	Cone-rod dystrophy (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	Peripheral neuropathy;C4520679:Abnormal macular morphology (1)
1	-	-	Retinal disorder (1)
1	-	-	Retinitis pigmentosa 19 (1)
1	-	-	Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.025	T
MetaSVM	Uncertain	0.063	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.84
MVP		0.93
MPC		0.46
ClinPred		0.063	T
GERP RS		4.9
Varity_R		0.83
gMVP		0.91
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		2.0
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76157638; hg19: chr1-94517254; COSMIC: COSV64675027;