rs472908

Variant names:

• chr1-94021798-G-A
• rs472908
• NM_000350.3:c.4773+48C>T

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.4773+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,606,414 control chromosomes in the GnomAD database, including 269,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29725 hom., cov: 31)
  • Exomes 𝑓: 0.57 (239847 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.444
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-94021798-G-A is Benign according to our data. Variant chr1-94021798-G-A is described in ClinVar as Benign. ClinVar VariationId is 99319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 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.4773+48C>T		intron	N/A	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.4551+48C>T		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.4773+48C>T		intron	N/A	ENSP00000359245.3	P78363
	ABCA4	ENST00000460514.1	TSL:5	n.267+48C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94022 AN: 151824 Hom.: 29678 Cov.: 31

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.583

GnomAD2 exomes AF: 0.584 AC: 146325 AN: 250422 AF XY: 0.578

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.608

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.572 AC: 831607 AN: 1454472 Hom.: 239847 Cov.: 31 AF XY: 0.571 AC XY: 413306 AN XY: 724100

African (AFR) AF: 0.755 AC: 25188 AN: 33340

American (AMR) AF: 0.661 AC: 29564 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16260 AN: 26094

East Asian (EAS) AF: 0.463 AC: 18350 AN: 39660

South Asian (SAS) AF: 0.552 AC: 47538 AN: 86108

European-Finnish (FIN) AF: 0.605 AC: 32341 AN: 53418

Middle Eastern (MID) AF: 0.574 AC: 3298 AN: 5746

European-Non Finnish (NFE) AF: 0.565 AC: 624321 AN: 1105214

Other (OTH) AF: 0.577 AC: 34747 AN: 60196

GnomAD4 genome AF: 0.620 AC: 94129 AN: 151942 Hom.: 29725 Cov.: 31 AF XY: 0.621 AC XY: 46083 AN XY: 74232

African (AFR) AF: 0.742 AC: 30750 AN: 41434

American (AMR) AF: 0.607 AC: 9267 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2163 AN: 3466

East Asian (EAS) AF: 0.454 AC: 2336 AN: 5146

South Asian (SAS) AF: 0.543 AC: 2609 AN: 4806

European-Finnish (FIN) AF: 0.620 AC: 6539 AN: 10544

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38600 AN: 67958

Other (OTH) AF: 0.588 AC: 1239 AN: 2106

Alfa AF: 0.578 Hom.: 59580

Bravo AF: 0.627

Asia WGS AF: 0.527 AC: 1833 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (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	-0.84
CADD	Benign	0.80
DANN	Benign	0.56
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs472908; hg19: chr1-94487354; COSMIC: COSV64672019; COSMIC: COSV64672019;