1-94008308-C-T

Variant names:

• chr1-94008308-C-T
• rs1800739
• NM_000350.3:c.5836-11G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):​c.5836-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,608,016 control chromosomes in the GnomAD database, including 27,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3134 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24290 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Scores: Splicing: ADA: 0.00001273
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:2
• Conservation: PhyloP100: 0.0540
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-94008308-C-T is Benign according to our data. Variant chr1-94008308-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.5836-11G>A		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.5614-11G>A		intron	N/A	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.5836-11G>A		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000465352.1	TSL:5	n.252-11G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30230 AN: 151742 Hom.: 3121 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.174 AC: 43794 AN: 251210 AF XY: 0.172

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.179 AC: 260223 AN: 1456156 Hom.: 24290 Cov.: 33 AF XY: 0.177 AC XY: 128452 AN XY: 724644

African (AFR) AF: 0.270 AC: 9015 AN: 33370

American (AMR) AF: 0.160 AC: 7164 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5323 AN: 26098

East Asian (EAS) AF: 0.136 AC: 5380 AN: 39674

South Asian (SAS) AF: 0.132 AC: 11418 AN: 86178

European-Finnish (FIN) AF: 0.176 AC: 9411 AN: 53382

Middle Eastern (MID) AF: 0.172 AC: 991 AN: 5754

European-Non Finnish (NFE) AF: 0.182 AC: 200911 AN: 1106830

Other (OTH) AF: 0.176 AC: 10610 AN: 60176

GnomAD4 genome AF: 0.199 AC: 30295 AN: 151860 Hom.: 3134 Cov.: 32 AF XY: 0.197 AC XY: 14591 AN XY: 74208

African (AFR) AF: 0.260 AC: 10750 AN: 41368

American (AMR) AF: 0.167 AC: 2556 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3468

East Asian (EAS) AF: 0.130 AC: 668 AN: 5140

South Asian (SAS) AF: 0.130 AC: 624 AN: 4812

European-Finnish (FIN) AF: 0.172 AC: 1813 AN: 10534

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12586 AN: 67942

Other (OTH) AF: 0.187 AC: 396 AN: 2114

Alfa AF: 0.197 Hom.: 1598

Bravo AF: 0.202

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (4)
-	-	1	ABCA4-related disorder (1)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinitis pigmentosa 19 (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.54
PhyloP100		0.054
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs1800739; hg19: chr1-94473864; COSMIC: COSV64672037; COSMIC: COSV64672037;