1-94008896-T-G

Variant names:

• chr1-94008896-T-G
• rs4147856
• NM_000350.3:c.5715-25A>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.5715-25A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,608,624 control chromosomes in the GnomAD database, including 29,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3146 hom., cov: 30)
  • Exomes 𝑓: 0.19 (26392 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -3.85
• Publications: 12 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 1-94008896-T-G is Benign according to our data. Variant chr1-94008896-T-G is described in ClinVar as Benign. ClinVar VariationId is 99404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 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.5715-25A>C		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.5493-25A>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.5715-25A>C		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000465352.1	TSL:5	n.131-25A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30336 AN: 150944 Hom.: 3131 Cov.: 30

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.190 AC: 47287 AN: 248922 AF XY: 0.184

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.187 AC: 273237 AN: 1457562 Hom.: 26392 Cov.: 33 AF XY: 0.186 AC XY: 134601 AN XY: 725322

African (AFR) AF: 0.248 AC: 8313 AN: 33466

American (AMR) AF: 0.241 AC: 10776 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5401 AN: 26128

East Asian (EAS) AF: 0.136 AC: 5400 AN: 39680

South Asian (SAS) AF: 0.136 AC: 11694 AN: 86250

European-Finnish (FIN) AF: 0.179 AC: 8888 AN: 49750

Middle Eastern (MID) AF: 0.174 AC: 1001 AN: 5766

European-Non Finnish (NFE) AF: 0.190 AC: 210641 AN: 1111478

Other (OTH) AF: 0.184 AC: 11123 AN: 60332

GnomAD4 genome AF: 0.201 AC: 30403 AN: 151062 Hom.: 3146 Cov.: 30 AF XY: 0.198 AC XY: 14619 AN XY: 73746

African (AFR) AF: 0.240 AC: 9843 AN: 41060

American (AMR) AF: 0.208 AC: 3152 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 740 AN: 3466

East Asian (EAS) AF: 0.131 AC: 671 AN: 5130

South Asian (SAS) AF: 0.129 AC: 614 AN: 4748

European-Finnish (FIN) AF: 0.172 AC: 1802 AN: 10450

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.192 AC: 13006 AN: 67780

Other (OTH) AF: 0.194 AC: 406 AN: 2088

Alfa AF: 0.195 Hom.: 4646

Bravo AF: 0.208

Asia WGS AF: 0.161 AC: 561 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Age related macular degeneration 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Severe early-childhood-onset retinal dystrophy Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa 19 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-rod dystrophy 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

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	-0.83
CADD	Benign	0.0020
DANN	Benign	0.74
PhyloP100		-3.9
Mutation Taster		=98/2	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: rs4147856; hg19: chr1-94474452; COSMIC: COSV64672050; COSMIC: COSV64672050;