rs62646863

Variant names:

• chr1-94103119-T-C
• rs62646863
• NM_000350.3:c.466A>G

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.466A>G​(p.Ile156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,124 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. I156I) has been classified as Likely benign. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:8 O:1
• Conservation: PhyloP100: 0.761
• Publications: 19 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 -10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009164572).
• BP6: Variant 1-94103119-T-C is Benign according to our data. Variant chr1-94103119-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99310.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00218 (332/152338) while in subpopulation AMR AF = 0.0106 (162/15298). AF 95% confidence interval is 0.00926. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• 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.466A>G	p.Ile156Val	missense	Exon 5 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.466A>G	p.Ile156Val	missense	Exon 5 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.466A>G	p.Ile156Val	missense	Exon 5 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.466A>G	p.Ile156Val	missense	Exon 5 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00147 AC: 370 AN: 251380 AF XY: 0.00149

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00197 AC: 2883 AN: 1461786 Hom.: 9 Cov.: 32 AF XY: 0.00190 AC XY: 1384 AN XY: 727212

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.00400 AC: 179 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

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

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53398

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00226 AC: 2509 AN: 1111944

Other (OTH) AF: 0.00229 AC: 138 AN: 60390

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74496

African (AFR) AF: 0.000289 AC: 12 AN: 41570

American (AMR) AF: 0.0106 AC: 162 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68044

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00262

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	5	not provided (10)
-	-	2	ABCA4-related disorder (2)
-	1	-	Abnormal retinal morphology (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)
-	1	-	Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	5.0
DANN	Benign	0.76
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.76
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.51
Sift	Benign	0.70	T
Sift4G	Benign	0.55	T
Polyphen		0.0020	B
Vest4		0.67
MVP		0.58
MPC		0.073
ClinPred		0.020	T
GERP RS		-1.2
Varity_R		0.036
gMVP		0.48
Mutation Taster		=92/8	polymorphism

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: rs62646863; hg19: chr1-94568675;