rs201117452

Positions:

chr1-94078652-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_000350.3(ABCA4):c.1294G>A(p.Glu432Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,499,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.83

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 links:

LOC124904222 (HGNC:):

LOC124904222 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3

BP4

Computational evidence support a benign effect (MetaRNN=0.042657107).

BP6

Variant 1-94078652-C-T is Benign according to our data. Variant chr1-94078652-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCA4	NM_000350.3 linkuse as main transcript	c.1294G>A	p.Glu432Lys	missense_variant	10/50	ENST00000370225.4
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-5077C>T		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1 linkuse as main transcript	c.1294G>A	p.Glu432Lys	missense_variant	10/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1294G>A	p.Glu432Lys	missense_variant	10/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1294G>A	p.Glu432Lys	missense_variant	10/19

Frequencies

GnomAD3 genomes

AF:

0.000109

AC:

AN:

137574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00353

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251490

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00212

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

152

AN:

1362088

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

676196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00484

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000743

GnomAD4 genome

AF:

0.000109

AC:

AN:

137664

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

65620

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00354

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed with two other variants in the ABCA4 gene in an individual with Stargardt disease in published literature, but it is not known what combination of the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sung et al., 2019); This variant is associated with the following publications: (PMID: 23424971, 29975949, 33090715, 33301772) -

Severe early-childhood-onset retinal dystrophy

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

0.0019

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.043

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

N;.

REVEL

Pathogenic

0.66

Sift

Benign

0.17

T;.

Sift4G

Benign

0.19

T;.

Polyphen

0.0020

B;.

Vest4

0.75

MVP

0.83

MPC

0.097

ClinPred

0.13

GERP RS

4.6

Varity_R

0.24

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over