rs61751374

Variant names:

• chr1-94043413-G-A
• rs61751374
• NM_000350.3:c.3113C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 15P and 2B. PS3 PM1 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000350.3(ABCA4):​c.3113C>T​(p.Ala1038Val) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,614,144 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001142302: Functional studies demonstrate that both the L541P/A1038V complex allele as well as the L541P and A1038V variants independently result in reduced ATPase activity" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1038A) has been classified as Likely benign. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:43 O:1
• Conservation: PhyloP100: 5.79
• Publications: 167 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001142302: Functional studies demonstrate that both the L541P/A1038V complex allele as well as the L541P and A1038V variants independently result in reduced ATPase activity; however, the affect of A1038V is milder compared to that of L541P alone or the L541P/A1038V complex allele (PMID: 11017087; 16103129; 25712131).; SCV002769511: Using transfected HEK293 cells the authors demonstrated that this variant slightly reduced ATPase activity and that the mutant protein retained major structural features similar to that of wild-type (PMID: 25712131).; SCV006584027: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11017087, 16103129, 25712131)."; SCV000511890: Functional studies demonstrate that the p.(L541P)/p.(A1038V) complex allele as well as the p.(L541P) and p.(A1038V) variants independently result in reduced ATPase activity; however, the affect of p.(A1038V) is milder compared to that of p.(L541P) alone or the p.(L541P)/p.(A1038V) complex allele (PMID: 25712131, 11017087, 16103129); SCV001417577: Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087, 16103129, 25712131).; SCV000914431: Expression in Xenopus laevis rods showed that the complex allele and second missense variant result in mislocalization of the protein, but the p.Ala1038Val variant protein had wild type localization. In the same study, expression in COS7 cells revealed that the rate of ATP hydrolysis of the complex allele is 68.1% of wild type (Wiszniewski et al. 2005).; SCV000711770: "In vitro functional studies provide some evidence that the p.Ala1038Val variant may impact protein function." PMID:11017087; SCV000883315: Functional analyses indicate a defect in ATP hydrolysis (Sun 2000, Zhang 2015).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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.
• PP5: Variant 1-94043413-G-A is Pathogenic according to our data. Variant chr1-94043413-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.023493528). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited 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.3113C>T	p.Ala1038Val	missense	Exon 21 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.2891C>T	p.Ala964Val	missense	Exon 20 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.3113C>T	p.Ala1038Val	missense	Exon 21 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00168 AC: 422 AN: 251308 AF XY: 0.00157

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00187 AC: 2734 AN: 1461888 Hom.: 7 Cov.: 31 AF XY: 0.00187 AC XY: 1359 AN XY: 727246

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00537 AC: 287 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00204 AC: 2273 AN: 1112012

Other (OTH) AF: 0.00166 AC: 100 AN: 60396

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74452

African (AFR) AF: 0.000337 AC: 14 AN: 41554

American (AMR) AF: 0.000916 AC: 14 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00622 AC: 66 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00135

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Severe early-childhood-onset retinal dystrophy (13)
8	-	-	not provided (9)
4	-	-	Retinal dystrophy (4)
3	-	-	Stargardt disease (3)
2	-	-	ABCA4-related disorder (2)
2	-	-	Age related macular degeneration 2 (2)
2	-	-	Cone-rod dystrophy 3 (2)
2	-	-	Macular dystrophy (2)
2	-	-	Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 (2)
1	-	-	Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 (1)
1	-	-	not specified (1)
1	-	-	Optic atrophy (1)
1	-	-	Retinal disorder (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0029	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.53
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.74
MVP		0.91
MPC		0.20
ClinPred		0.019	T
GERP RS		5.9
Varity_R		0.39
gMVP		0.81
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61751374; hg19: chr1-94508969;