rs77293072

Variant names:

• chr1-93996193-C-T
• rs77293072
• NM_000350.3:c.6732G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.6732G>A​(p.Val2244Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,611,904 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (151 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (156 hom.)
• Consequence: ABCA4 NM_000350.3 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.451
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-93996193-C-T is Benign according to our data. Variant chr1-93996193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.451 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 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.6732G>A	p.Val2244Val	splice_region synonymous	Exon 49 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.6510G>A	p.Val2170Val	splice_region synonymous	Exon 48 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.6732G>A	p.Val2244Val	splice_region synonymous	Exon 49 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3654 AN: 152198 Hom.: 152 Cov.: 33

Gnomad AFR AF: 0.0834

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00791

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00650 AC: 1632 AN: 251020 AF XY: 0.00509

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00256 AC: 3735 AN: 1459588 Hom.: 156 Cov.: 30 AF XY: 0.00222 AC XY: 1615 AN XY: 726242

African (AFR) AF: 0.0886 AC: 2948 AN: 33272

American (AMR) AF: 0.00570 AC: 255 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1110396

Other (OTH) AF: 0.00517 AC: 312 AN: 60338

GnomAD4 genome AF: 0.0240 AC: 3653 AN: 152316 Hom.: 151 Cov.: 33 AF XY: 0.0234 AC XY: 1741 AN XY: 74486

African (AFR) AF: 0.0831 AC: 3452 AN: 41538

American (AMR) AF: 0.00790 AC: 121 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68042

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0157 Hom.: 145

Bravo AF: 0.0267

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	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
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.12
DANN	Benign	0.40
PhyloP100		-0.45
Mutation Taster		=89/11	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: rs77293072; hg19: chr1-94461749; COSMIC: COSV64675913;