chr1-94048921-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_StrongBP6BS2_Supporting

The NM_000350.3(ABCA4):c.2690C>T(p.Thr897Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,066 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T897T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:8O:1

Conservation

PhyloP100: 2.35

Publications

19 publications found

Variant links:

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
age related macular degeneration 2
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.

BP4

Computational evidence support a benign effect (MetaRNN=0.009508371).

BP6

Variant 1-94048921-G-A is Benign according to our data. Variant chr1-94048921-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99153.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.2690C>T	p.Thr897Ile	missense	Exon 18 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.2468C>T	p.Thr823Ile	missense	Exon 17 of 49	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.2690C>T	p.Thr897Ile	missense	Exon 18 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.2468C>T	p.Thr823Ile	missense	Exon 17 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

197

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00122

AC:

308

AN:

251454

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00146

AC:

2129

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1059

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000984

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00566

AC:

148

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000278

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00158

AC:

1759

AN:

1112000

Other (OTH)

AF:

0.00174

AC:

105

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

109

218

327

436

545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152188

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41502

American (AMR)

AF:

0.00229

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00179

AC:

122

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00114

AC:

138

EpiCase

AF:

0.00207

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

ABCA4-related disorder (1)

Age related macular degeneration 2 (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

Retinal dystrophy (1)

Retinitis Pigmentosa, Recessive (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.73

M_CAP

Benign

0.027

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.7

PhyloP100

2.4

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.62

Sift

Benign

0.19

Sift4G

Benign

0.20

Polyphen

0.054

Vest4

0.80

MVP

0.94

MPC

0.30

ClinPred

0.022

GERP RS

5.3

Varity_R

0.11

gMVP

0.67

Mutation Taster

=61/39

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over