rs6657239

Variant names:

• chr1-94098927-C-T
• rs6657239
• NM_000350.3:c.635G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-94098927-C-T
• chr1-94098927-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1 PM5 PP2 BP4_Strong BP6 BA1

The NM_000350.3(ABCA4):​c.635G>A​(p.Arg212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,470 control chromosomes in the GnomAD database, including 1,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.049 (184 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1217 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13 O:1
• Conservation: PhyloP100: 3.20
• Publications: 36 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: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94098928-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7898.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 cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.017632037).
• BP6: Variant 1-94098927-C-T is Benign according to our data. Variant chr1-94098927-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99454.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

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.635G>A	p.Arg212His	missense	Exon 6 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.635G>A	p.Arg212His	missense	Exon 6 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.635G>A	p.Arg212His	missense	Exon 6 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.635G>A	p.Arg212His	missense	Exon 6 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7389 AN: 152150 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0397

GnomAD2 exomes AF: 0.0411 AC: 10284 AN: 250264 AF XY: 0.0390

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0614

Gnomad FIN exome AF: 0.0610

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0388 AC: 56713 AN: 1461202 Hom.: 1217 Cov.: 32 AF XY: 0.0378 AC XY: 27470 AN XY: 726830

African (AFR) AF: 0.0710 AC: 2377 AN: 33480

American (AMR) AF: 0.0406 AC: 1815 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 824 AN: 26132

East Asian (EAS) AF: 0.0615 AC: 2443 AN: 39700

South Asian (SAS) AF: 0.0225 AC: 1938 AN: 86256

European-Finnish (FIN) AF: 0.0607 AC: 3202 AN: 52762

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5768

European-Non Finnish (NFE) AF: 0.0371 AC: 41282 AN: 1111994

Other (OTH) AF: 0.0434 AC: 2624 AN: 60392

GnomAD4 genome AF: 0.0486 AC: 7400 AN: 152268 Hom.: 184 Cov.: 33 AF XY: 0.0486 AC XY: 3617 AN XY: 74456

African (AFR) AF: 0.0683 AC: 2838 AN: 41534

American (AMR) AF: 0.0477 AC: 730 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.0582 AC: 301 AN: 5172

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4826

European-Finnish (FIN) AF: 0.0544 AC: 577 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0379 AC: 2576 AN: 68032

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0384 Hom.: 435

Bravo AF: 0.0476

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0384 AC: 148

ESP6500AA AF: 0.0706 AC: 311

ESP6500EA AF: 0.0341 AC: 293

ExAC AF: 0.0403 AC: 4898

Asia WGS AF: 0.0530 AC: 187 AN: 3478

EpiCase AF: 0.0364

EpiControl AF: 0.0359

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	1	ABCA4-related disorder (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.72
Sift	Benign	0.061	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.42
MPC		0.12
ClinPred		0.041	T
GERP RS		4.0
Varity_R		0.058
gMVP		0.85
Mutation Taster		=79/21	polymorphism (auto)

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: rs6657239; hg19: chr1-94564483; COSMIC: COSV64673474;