NM_000350.3:c.618C>G

Variant names:

• chr1-94098944-G-C
• rs61748536
• NM_000350.3:c.618C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 7P and 12B. PS3 PM1 PP2 BP4_Strong BS1 BS2

The NM_000350.3(ABCA4):​c.618C>G​(p.Ser206Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,612,628 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000321328: Published functional studies demonstrate a damaging effect with reduced ATPase activity compared to wild type. PMID:11017087". Synonymous variant affecting the same amino acid position (i.e. S206S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2 O:1
• Conservation: PhyloP100: 0.125
• Publications: 14 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: Likely_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321328: Published functional studies demonstrate a damaging effect with reduced ATPase activity compared to wild type. PMID:11017087
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009199023).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (693/152300) while in subpopulation AFR AF = 0.0159 (661/41564). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.618C>G	p.Ser206Arg	missense	Exon 6 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.618C>G	p.Ser206Arg	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.618C>G	p.Ser206Arg	missense	Exon 6 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.618C>G	p.Ser206Arg	missense	Exon 6 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00107 AC: 266 AN: 249070 AF XY: 0.000757

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000477 AC: 696 AN: 1460328 Hom.: 4 Cov.: 32 AF XY: 0.000423 AC XY: 307 AN XY: 726400

African (AFR) AF: 0.0177 AC: 593 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51908

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111992

Other (OTH) AF: 0.00103 AC: 62 AN: 60380

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152300 Hom.: 6 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74468

African (AFR) AF: 0.0159 AC: 661 AN: 41564

American (AMR) AF: 0.00137 AC: 21 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.0000244 Hom.: 0

Bravo AF: 0.00527

ExAC AF: 0.00134 AC: 163

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	ABCA4-related disorder (2)
1	-	1	not provided (3)
-	1	1	not specified (2)
-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.13
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.73
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.82		Loss of helix (P = 0.0196)
MVP		0.91
MPC		0.35
ClinPred		0.13	T
GERP RS		-4.1
Varity_R		0.18
gMVP		0.84
Mutation Taster		=47/53	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: rs61748536; hg19: chr1-94564500; COSMIC: COSV64674353;