rs190540405

Positions:

• chr1-94080705-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BP4_Strong

The NM_000350.3(ABCA4):​c.872C>T​(p.Pro291Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P291A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.414

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]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a disulfide_bond (size 249) in uniprot entity ABCA4_HUMAN there are 150 pathogenic changes around while only 8 benign (95%) in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94080706-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.015607595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.872C>T	p.Pro291Leu	missense_variant	8/50	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1	n.203-3024G>A		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1	c.872C>T	p.Pro291Leu	missense_variant	8/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.872C>T	p.Pro291Leu	missense_variant	8/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1	c.872C>T	p.Pro291Leu	missense_variant	8/19			ENSP00000496882

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000643 AC: 161 AN: 250402 Hom.: 1 AF XY: 0.000480 AC XY: 65 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000159 AC: 232 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.000149 AC XY: 108 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74400

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000754 Hom.: 0

Bravo AF: 0.000287

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	Identified in patients with a broad range of ABCA4-related disorders (Early-onset Stargardt disease, Stargardt macular dystrophy, Cone-rod dystrophy, Macular dystrophy) in published literature (Ernest et al., 2009; Jiang et al., 2016; Birtel et al., 2018; Roberts et al., 2012; Lambertus et al., 2015); Identified in patients with ABCA4-related disorders who also harbored multiple other ABCA4 variants, phase unknown in published literature (Jiang et al., 2016; Birtel et al., 2018; Lambertus et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20029649, 31456290, 26780318, 29925512, 29555955, 30903310, 25444351, 22328824) -

ABCA4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 25, 2018

The ABCA4c.872C>T (p.Pro291Leu) missense variant has been reported in four studies, in which it is found in a total of five individuals with Stargardt disease, including in three in a compound heterozygous state and in two in a heterozygous state (Ernest et al. 2009; Roberts et al. 2012; Teussink et al. 2015; Nassisi et al. 2018). The variant has not been reported in the literature in association with autosomal recessive cone rod dystrophy, autosomal recessive retinitis pigmentosa, or autosomal dominant macular degeneration. The p.Pro291Leu variant was absent from 100 controls and is reported at a frequency of 0.004409 in the Latino population of the Exome Aggregation Consortium. Based on the limited evidence the p.Pro291Leu is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.076	T;.
Sift4G	Benign	0.091	T;.
Polyphen		0.93	P;.
Vest4		0.76
MVP		0.93
MPC		0.23
ClinPred		0.043	T
GERP RS		3.8
Varity_R		0.077
gMVP		0.65

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: rs190540405; hg19: chr1-94546261;