rs61754022

Variant names:

• chr1-94062803-C-T
• rs61754022
• NM_000350.3:c.1761-50G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000350.3(ABCA4):​c.1761-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,585,642 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.017 (243 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.0770
• Publications: 2 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=-0.86).
• BP6: Variant 1-94062803-C-T is Benign according to our data. Variant chr1-94062803-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94062803-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94062803-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94062803-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1848/152240) while in subpopulation NFE AF = 0.0194 (1320/68014). AF 95% confidence interval is 0.0185. There are 12 homozygotes in GnomAd4. There are 879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1761-50G>A		intron_variant	Intron 12 of 49	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1761-50G>A		intron_variant	Intron 12 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1761-50G>A		intron_variant	Intron 12 of 49	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1761-50G>A		intron_variant	Intron 12 of 18			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1847 AN: 152122 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0141 AC: 3236 AN: 228846 AF XY: 0.0144

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0168 AC: 24061 AN: 1433402 Hom.: 243 Cov.: 28 AF XY: 0.0168 AC XY: 11999 AN XY: 712904

African (AFR) AF: 0.00240 AC: 79 AN: 32900

American (AMR) AF: 0.0108 AC: 467 AN: 43334

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 630 AN: 25776

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39276

South Asian (SAS) AF: 0.00957 AC: 806 AN: 84212

European-Finnish (FIN) AF: 0.0116 AC: 591 AN: 51062

Middle Eastern (MID) AF: 0.0276 AC: 158 AN: 5720

European-Non Finnish (NFE) AF: 0.0186 AC: 20342 AN: 1091594

Other (OTH) AF: 0.0166 AC: 986 AN: 59528

GnomAD4 genome AF: 0.0121 AC: 1848 AN: 152240 Hom.: 12 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74432

African (AFR) AF: 0.00310 AC: 129 AN: 41548

American (AMR) AF: 0.00961 AC: 147 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4818

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0194 AC: 1320 AN: 68014

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0187 Hom.: 3

Bravo AF: 0.0117

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		0.077
Mutation Taster		=99/1	polymorphism

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: rs61754022; hg19: chr1-94528359; COSMIC: COSV64676956; COSMIC: COSV64676956;