rs1800699

Variant names:

• chr1-93997840-G-A
• rs1800699
• NM_000350.3:c.6729+21C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-93997840-G-A
• chr1-93997840-G-C

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.6729+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,726 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (52 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.981
• Publications: 7 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=-0.83).
• BP6: Variant 1-93997840-G-A is Benign according to our data. Variant chr1-93997840-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00972 (1479/152186) while in subpopulation AFR AF = 0.0265 (1099/41522). AF 95% confidence interval is 0.0252. There are 12 homozygotes in GnomAd4. There are 715 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

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.6729+21C>T		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.6507+21C>T		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.6729+21C>T		intron	N/A	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1476 AN: 152068 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0117

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00596 AC: 1494 AN: 250500 AF XY: 0.00616

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00348 AC: 5084 AN: 1461540 Hom.: 52 Cov.: 31 AF XY: 0.00380 AC XY: 2761 AN XY: 727054

African (AFR) AF: 0.0291 AC: 974 AN: 33466

American (AMR) AF: 0.00237 AC: 106 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 606 AN: 26134

East Asian (EAS) AF: 0.00297 AC: 118 AN: 39696

South Asian (SAS) AF: 0.0126 AC: 1084 AN: 86160

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53336

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5748

European-Non Finnish (NFE) AF: 0.00156 AC: 1730 AN: 1111908

Other (OTH) AF: 0.00576 AC: 348 AN: 60376

GnomAD4 genome AF: 0.00972 AC: 1479 AN: 152186 Hom.: 12 Cov.: 32 AF XY: 0.00961 AC XY: 715 AN XY: 74410

African (AFR) AF: 0.0265 AC: 1099 AN: 41522

American (AMR) AF: 0.00536 AC: 82 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0117 AC: 56 AN: 4782

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68010

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00875 Hom.: 2

Bravo AF: 0.0106

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.45
PhyloP100		-0.98
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: rs1800699; hg19: chr1-94463396;