chr1-94111412-T-C

Variant names:

• chr1-94111412-T-C
• rs2297634
• NM_000350.3:c.302+26A>G

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.302+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,611,446 control chromosomes in the GnomAD database, including 204,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18790 hom., cov: 33)
  • Exomes 𝑓: 0.50 (185330 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -2.79
• Publications: 22 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=-0.93).
• BP6: Variant 1-94111412-T-C is Benign according to our data. Variant chr1-94111412-T-C is described in ClinVar as Benign. ClinVar VariationId is 99189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 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.302+26A>G		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.302+26A>G		intron	N/A	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.302+26A>G		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000649773.1		c.302+26A>G		intron	N/A	ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74938 AN: 152034 Hom.: 18759 Cov.: 33

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.520 AC: 129054 AN: 248258 AF XY: 0.518

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.613

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.646

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.502 AC: 732032 AN: 1459294 Hom.: 185330 Cov.: 43 AF XY: 0.503 AC XY: 364911 AN XY: 725820

African (AFR) AF: 0.446 AC: 14918 AN: 33456

American (AMR) AF: 0.606 AC: 26957 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10811 AN: 26102

East Asian (EAS) AF: 0.661 AC: 26213 AN: 39656

South Asian (SAS) AF: 0.577 AC: 49566 AN: 85886

European-Finnish (FIN) AF: 0.492 AC: 26252 AN: 53308

Middle Eastern (MID) AF: 0.390 AC: 2175 AN: 5578

European-Non Finnish (NFE) AF: 0.491 AC: 545386 AN: 1110538

Other (OTH) AF: 0.494 AC: 29754 AN: 60270

GnomAD4 genome AF: 0.493 AC: 75023 AN: 152152 Hom.: 18790 Cov.: 33 AF XY: 0.497 AC XY: 36967 AN XY: 74364

African (AFR) AF: 0.449 AC: 18626 AN: 41510

American (AMR) AF: 0.556 AC: 8510 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1444 AN: 3464

East Asian (EAS) AF: 0.657 AC: 3396 AN: 5166

South Asian (SAS) AF: 0.585 AC: 2819 AN: 4820

European-Finnish (FIN) AF: 0.495 AC: 5244 AN: 10588

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33432 AN: 67988

Other (OTH) AF: 0.482 AC: 1020 AN: 2114

Alfa AF: 0.482 Hom.: 30579

Bravo AF: 0.495

Asia WGS AF: 0.606 AC: 2108 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa 19 (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.027
DANN	Benign	0.18
PhyloP100		-2.8
Mutation Taster		=100/0	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: rs2297634; hg19: chr1-94576968; COSMIC: COSV64672458;