rs56142141

Positions:

chr1-94008290-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000350.3(ABCA4):c.5843C>T(p.Pro1948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,262 control chromosomes in the GnomAD database, including 1,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1948S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.031 ( 107 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1427 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11O:1

Conservation

PhyloP100: 2.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000350.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0034454763).

BP6

Variant 1-94008290-G-A is Benign according to our data. Variant chr1-94008290-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99413.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5, not_provided=1, Benign=5}. Variant chr1-94008290-G-A is described in Lovd as [Likely_benign]. Variant chr1-94008290-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.031 (4724/152224) while in subpopulation NFE AF= 0.0452 (3075/68010). AF 95% confidence interval is 0.0439. There are 107 homozygotes in gnomad4. There are 2259 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 107 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.5843C>T	p.Pro1948Leu	missense_variant	42/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.5621C>T	p.Pro1874Leu	missense_variant	41/49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.5843C>T	p.Pro1948Leu	missense_variant	42/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 link	n.259C>T		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4725

AN:

152106

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00780

Gnomad AMI

AF:

0.0549

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0565

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0335

GnomAD3 exomes

AF:

0.0314

AC:

7885

AN:

251428

Hom.:

143

AF XY:

0.0315

AC XY:

4280

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0260

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00719

Gnomad FIN exome

AF:

0.0588

Gnomad NFE exome

AF:

0.0438

Gnomad OTH exome

AF:

0.0380

GnomAD4 exome

AF:

0.0402

AC:

58669

AN:

1461038

Hom.:

1427

Cov.:

AF XY:

0.0393

AC XY:

28553

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.00699

Gnomad4 AMR exome

AF:

0.0262

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00774

Gnomad4 FIN exome

AF:

0.0564

Gnomad4 NFE exome

AF:

0.0459

Gnomad4 OTH exome

AF:

0.0347

GnomAD4 genome

AF:

0.0310

AC:

4724

AN:

152224

Hom.:

107

Cov.:

AF XY:

0.0303

AC XY:

2259

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00775

Gnomad4 AMR

AF:

0.0347

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00705

Gnomad4 FIN

AF:

0.0565

Gnomad4 NFE

AF:

0.0452

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0392

Hom.:

175

Bravo

AF:

0.0293

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.0374

AC:

322

ExAC

AF:

0.0306

AC:

3710

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0434

EpiControl

AF:

0.0451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	- -

Age related macular degeneration 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 21, 2020

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP3. -

Retinitis Pigmentosa, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Severe early-childhood-onset retinal dystrophy

Benign:1

Benign, no assertion criteria provided

research

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

- -

Cone-Rod Dystrophy, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Macular degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

0.0092

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Uncertain

0.044

MutationAssessor

Benign

2.0

.;M

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.53

.;N

REVEL

Uncertain

0.31

Sift

Benign

0.10

.;T

Sift4G

Benign

0.19

T;T

Polyphen

0.0020

.;B

Vest4

0.094

MPC

0.089

ClinPred

0.013

GERP RS

5.3

Varity_R

0.068

gMVP

0.73

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