rs41292677

Variant names:

• chr1-94001992-C-G
• rs41292677
• NM_000350.3:c.6148G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PM1 PP2 PP3 BP6_Very_Strong BS2

The NM_000350.3(ABCA4):​c.6148G>C​(p.Val2050Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,614,142 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★). The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: ABCA4 NM_000350.3 missense, splice_region
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Likely benign reviewed by expert panel P:5 U:11 B:8 O:1
• Conservation: PhyloP100: 7.45
• Publications: 58 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: Benign. The variant received -8 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, 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 1-94001992-C-G is Benign according to our data. Variant chr1-94001992-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 7884.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.6148G>C	p.Val2050Leu	missense splice_region	Exon 45 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5926G>C	p.Val1976Leu	missense splice_region	Exon 44 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.6148G>C	p.Val2050Leu	missense splice_region	Exon 45 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.564G>C		splice_region non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152144 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00297 AC: 746 AN: 251450 AF XY: 0.00274

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00370 AC: 5414 AN: 1461880 Hom.: 11 Cov.: 32 AF XY: 0.00350 AC XY: 2546 AN XY: 727240

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00615 AC: 275 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00585 AC: 153 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00424 AC: 4714 AN: 1112004

Other (OTH) AF: 0.00373 AC: 225 AN: 60396

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152262 Hom.: 2 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74452

African (AFR) AF: 0.000770 AC: 32 AN: 41552

American (AMR) AF: 0.00843 AC: 129 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68014

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00388

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00498

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (7)
3	1	-	Severe early-childhood-onset retinal dystrophy (4)
-	2	-	Retinal dystrophy (2)
-	1	-	ABCA4-related disorder (1)
-	-	1	ABCA4-related retinopathy (1)
1	-	-	Cone dystrophy (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	not specified (1)
-	1	-	Retinal disorder (1)
1	-	-	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (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)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.17	N
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.76
Sift	Benign	0.069	T
Sift4G	Benign	0.063	T
Polyphen		0.95	P
Vest4		0.78
MVP		0.90
MPC		0.46
ClinPred		0.047	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
Splicevardb		1.0
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: rs41292677; hg19: chr1-94467548;