1-93995982-G-A

Variant names:

• chr1-93995982-G-A
• rs4147872
• NM_000350.3:c.6816+127C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000350.3(ABCA4):​c.6816+127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 769,660 control chromosomes in the GnomAD database, including 15,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (8973 hom., cov: 32)
  • Exomes 𝑓: 0.10 (6357 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.25
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-93995982-G-A is Benign according to our data. Variant chr1-93995982-G-A is described in ClinVar as [Benign]. Clinvar id is 1248438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.6816+127C>T		intron_variant	Intron 49 of 49	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.6594+127C>T		intron_variant	Intron 48 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.6816+127C>T		intron_variant	Intron 49 of 49	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36779 AN: 151974 Hom.: 8952 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.104 AC: 64255 AN: 617568 Hom.: 6357 AF XY: 0.100 AC XY: 32711 AN XY: 325510

African (AFR) AF: 0.627 AC: 10576 AN: 16868

American (AMR) AF: 0.213 AC: 7204 AN: 33810

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 2612 AN: 18984

East Asian (EAS) AF: 0.108 AC: 3479 AN: 32266

South Asian (SAS) AF: 0.0897 AC: 5532 AN: 61640

European-Finnish (FIN) AF: 0.0416 AC: 1450 AN: 34846

Middle Eastern (MID) AF: 0.153 AC: 384 AN: 2516

European-Non Finnish (NFE) AF: 0.0747 AC: 28731 AN: 384510

Other (OTH) AF: 0.133 AC: 4287 AN: 32128

GnomAD4 genome AF: 0.242 AC: 36859 AN: 152092 Hom.: 8973 Cov.: 32 AF XY: 0.238 AC XY: 17697 AN XY: 74356

African (AFR) AF: 0.630 AC: 26108 AN: 41440

American (AMR) AF: 0.200 AC: 3055 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.103 AC: 531 AN: 5160

South Asian (SAS) AF: 0.0980 AC: 473 AN: 4826

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10614

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.0760 AC: 5171 AN: 67996

Other (OTH) AF: 0.214 AC: 452 AN: 2108

Alfa AF: 0.117 Hom.: 1169

Bravo AF: 0.274

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.67
DANN	Benign	0.71
PhyloP100		-2.3
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: rs4147872; hg19: chr1-94461538;