rs56197337

Variant names:

• chr1-94060488-A-G
• rs56197337
• NM_000350.3:c.2160+49T>C

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.2160+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,560,890 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (258 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1817 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.238
• 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=-0.88).
• BP6: Variant 1-94060488-A-G is Benign according to our data. Variant chr1-94060488-A-G is described in ClinVar as Benign. ClinVar VariationId is 255917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0715 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.2160+49T>C		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.2160+49T>C		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.2160+49T>C		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000649773.1		c.2160+49T>C		intron	N/A	ENSP00000496882.1
	ABCA4	ENST00000472033.1	TSL:3	n.280+49T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8230 AN: 152176 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0554

GnomAD2 exomes AF: 0.0499 AC: 12426 AN: 249258 AF XY: 0.0492

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.0719

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0404

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0442

GnomAD4 exome AF: 0.0490 AC: 69055 AN: 1408596 Hom.: 1817 Cov.: 26 AF XY: 0.0487 AC XY: 34257 AN XY: 704014

African (AFR) AF: 0.0720 AC: 2324 AN: 32256

American (AMR) AF: 0.0711 AC: 3173 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 549 AN: 25818

East Asian (EAS) AF: 0.0427 AC: 1684 AN: 39400

South Asian (SAS) AF: 0.0561 AC: 4765 AN: 84884

European-Finnish (FIN) AF: 0.0440 AC: 2348 AN: 53392

Middle Eastern (MID) AF: 0.0373 AC: 154 AN: 4132

European-Non Finnish (NFE) AF: 0.0480 AC: 51176 AN: 1065594

Other (OTH) AF: 0.0492 AC: 2882 AN: 58520

GnomAD4 genome AF: 0.0543 AC: 8266 AN: 152294 Hom.: 258 Cov.: 32 AF XY: 0.0545 AC XY: 4056 AN XY: 74486

African (AFR) AF: 0.0687 AC: 2855 AN: 41552

American (AMR) AF: 0.0751 AC: 1149 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.0376 AC: 195 AN: 5184

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4822

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3135 AN: 68028

Other (OTH) AF: 0.0553 AC: 117 AN: 2116

Alfa AF: 0.0473 Hom.: 37

Bravo AF: 0.0574

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.68
PhyloP100		0.24
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: rs56197337; hg19: chr1-94526044;