1-94040048-A-C

Position:

chr1-94040048-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.3602T>G(p.Leu1201Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00498 in 1,603,546 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1201L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 212 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 157 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:15O:1

Conservation

PhyloP100: 5.03

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:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025280416).

BP6

Variant 1-94040048-A-C is Benign according to our data. Variant chr1-94040048-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 7903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94040048-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94040048-A-C is described in Lovd as [Likely_benign]. Variant chr1-94040048-A-C is described in Lovd as [Pathogenic]. Variant chr1-94040048-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.3602T>G	p.Leu1201Arg	missense_variant	24/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.3380T>G	p.Leu1127Arg	missense_variant	23/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.3602T>G	p.Leu1201Arg	missense_variant	24/50	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

4043

AN:

152052

Hom.:

211

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0936

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00667

AC:

1566

AN:

234950

Hom.:

AF XY:

0.00499

AC XY:

631

AN XY:

126528

show subpopulations

Gnomad AFR exome

AF:

0.0954

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000710

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00463

GnomAD4 exome

AF:

0.00272

AC:

3943

AN:

1451376

Hom.:

157

Cov.:

AF XY:

0.00242

AC XY:

1741

AN XY:

720738

show subpopulations

Gnomad4 AFR exome

AF:

0.0964

Gnomad4 AMR exome

AF:

0.00438

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000226

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.00585

GnomAD4 genome

AF:

0.0266

AC:

4046

AN:

152170

Hom.:

212

Cov.:

AF XY:

0.0259

AC XY:

1929

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0934

Gnomad4 AMR

AF:

0.00707

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00451

Hom.:

Bravo

AF:

0.0294

ESP6500AA

AF:

0.0935

AC:

412

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00808

AC:

980

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28559085, 20647261, 29925512, 25066811, 24011517, 23982839, 27884173, 9973280, 25097241, 16123440, 19074458, 20981092) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCA4 p.Leu1201Arg variant was identified in 19 of 988 proband chromosomes (frequency: 0.019) from individuals or families with Stargardt disease and cone-rod dystrophy (Schulz_2017_PMID:28118664; Utz_2013_PMID:24011517; Zernant_2014_PMID:25066811; Fishman_2003_PMID:12796258). The variant was identified in dbSNP (ID: rs61750126), ClinVar (classified as benign by EGL Genetics, likely benign by Illumina and likely pathogenic by Institute of Human Genetics, Univ. Regensburg) and LOVD 3.0 (classified as a VUS and likely benign). The variant was also identified in control databases in 2402 of 266312 chromosomes (114 homozygous) at a frequency of 0.009019 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2219 of 23326 chromosomes (freq: 0.09513), Other in 32 of 6916 chromosomes (freq: 0.004627), Latino in 133 of 34270 chromosomes (freq: 0.003881), European (non-Finnish) in 16 of 120738 chromosomes (freq: 0.000133) and South Asian in 2 of 28188 chromosomes (freq: 0.000071), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Leu1201 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Severe early-childhood-onset retinal dystrophy

Benign:2

Benign, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Cone-rod dystrophy 3

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Jun 01, 2003

- -

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 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

0.30

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.33

Eigen

Benign

0.023

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.56

Sift

Benign

0.23

Sift4G

Benign

0.51

Polyphen

0.031

Vest4

0.74

MVP

0.94

MPC

0.51

ClinPred

0.028

GERP RS

5.5

Varity_R

0.29

gMVP

0.59

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

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