rs61748549

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000350.3(ABCA4):c.1140T>A(p.Asn380Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,226 control chromosomes in the GnomAD database, including 2 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 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 2 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.47

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050882727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCA4	NM_000350.3 linkuse as main transcript	c.1140T>A	p.Asn380Lys	missense_variant	9/50	ENST00000370225.4
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-4308A>T		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1 linkuse as main transcript	c.1140T>A	p.Asn380Lys	missense_variant	9/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1140T>A	p.Asn380Lys	missense_variant	9/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1140T>A	p.Asn380Lys	missense_variant	9/19

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000549

AC:

138

AN:

251378

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000897

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000696

AC:

1017

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000693

AC XY:

504

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000820

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000617

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000934

Hom.:

Bravo

AF:

0.000790

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	Identified in patients with Stargardt disease and retinitis pigmentosa in published literature, however a second ABCA4 variant was not identified in these cases (Webster et al., 2001; Valverde et al., 2006; Valverde et al., 2007; Smaragda et al., 2018); Identified in a patient with retinitis pigmentosa in published literature who also had two loss-of-function variants in the CEP290 gene (Eisenberger et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18977788, 16917483, 17325136, 14709597, 34426522, 32641690, 29854428, 26355662, 11328725, 35836572, 32000842, 24265693) -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2016	- -

ABCA4-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 27, 2024	The ABCA4 c.1140T>A variant is predicted to result in the amino acid substitution p.Asn380Lys. This variant has been reported in multiple individuals with autosomal recessive retinal dystrophies (see for example, Table S1, Patel et al. 2015. PubMed ID: 26355662; Table 1, Riveiro-Alvarez et al 2013. PubMed ID: 23755871; Table S4, Maltese et al. 2022. PubMed ID: 35836572). However, in Riveiro-Alvarez et al. this variant was reported in cis with another variant as c.[1140T>A; 5395A>G] (p.[Asn380Lys; Asn1799Asp]). This variant is reported in 0.091% of alleles in individuals of European (non-Finnish) descent in gnomAD, indicating it is relatively common. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 10, 2015

- -

Severe early-childhood-onset retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 30, 2017

- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.13

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Benign

-0.096

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.051

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.013

D;.

Sift4G

Uncertain

0.021

D;.

Polyphen

0.34

B;.

Vest4

0.75

MutPred

0.79

Gain of catalytic residue at N380 (P = 0.0069);Gain of catalytic residue at N380 (P = 0.0069);

MVP

0.88

MPC

0.39

ClinPred

0.077

GERP RS

1.4

Varity_R

0.47

gMVP

0.89

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