rs56142141

chr1-94008290-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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. 11/19 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 same amino acid change has been previously reported as Likely benignin 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10 O:1
• Conservation: PhyloP100: 2.29

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]

ACMG classification

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, 2 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: {Benign=5, not_provided=1, Uncertain_significance=1, Likely_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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 107 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.5843C>T	p.Pro1948Leu	missense_variant	42/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.5621C>T	p.Pro1874Leu	missense_variant	41/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.5843C>T	p.Pro1948Leu	missense_variant	42/50	1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.259C>T		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4725 AN: 152106 Hom.: 107 Cov.: 32

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

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.: 33 AF XY: 0.0393 AC XY: 28553 AN XY: 726844

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.: 32 AF XY: 0.0303 AC XY: 2259 AN XY: 74436

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: 43

ESP6500EA AF: 0.0374 AC: 322

ExAC AF: 0.0306 AC: 3710

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2017	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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 Disorders 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. -

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	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	0.0092
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Uncertain	0.044	D
MutationTaster	Benign	0.83	D;N;N
PrimateAI	Benign	0.31	T
REVEL	Uncertain	0.31
Sift4G	Benign	0.19	T;T
Polyphen		0.0020	.;B
Vest4		0.094
MPC		0.089
ClinPred		0.013	T
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

Other links and lift over

dbSNP: rs56142141; hg19: chr1-94473846; COSMIC: COSV64673479; COSMIC: COSV64673479;