rs145525174

chr1-94063218-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000350.3(ABCA4):c.1654G>A(p.Val552Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,084 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V552A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:9
• Conservation: PhyloP100: 2.49

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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000350.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.013788432).
• BP6: Variant 1-94063218-C-T is Benign according to our data. Variant chr1-94063218-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94063218-C-T is described in Lovd as [Likely_benign]. Variant chr1-94063218-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94063218-C-T is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1654G>A	p.Val552Ile	missense_variant	12/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.1654G>A	p.Val552Ile	missense_variant	12/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1654G>A	p.Val552Ile	missense_variant	12/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1654G>A	p.Val552Ile	missense_variant	12/19

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00269 AC: 677 AN: 251436 Hom.: 2 AF XY: 0.00273 AC XY: 371 AN XY: 135888

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00463

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00385 AC: 5622 AN: 1461840 Hom.: 16 Cov.: 32 AF XY: 0.00383 AC XY: 2783 AN XY: 727228

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74438

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00432

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00374 Hom.: 3

Bravo AF: 0.00227

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00264 AC: 320

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00376

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ABCA4: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29386879, 31766579, 28559085, 30718709, 29925512, 19243736, 19028736, 10958763, 22229821, 29555955, 29847635, 28118664, 26593885, 26720470, 18024811, 24265693) -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

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

Jan 01, 2016

- -

Retinal dystrophy Uncertain:1

Uncertain significance, flagged submission

clinical testing

Blueprint Genetics

Jun 05, 2018

- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 09, 2017

- -

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

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

- -

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	0.088
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.75	N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.24	T;.
Sift4G	Benign	0.24	T;.
Polyphen		0.045	B;.
Vest4		0.28
MVP		0.78
MPC		0.16
ClinPred		0.034	T
GERP RS		4.0
Varity_R		0.063
gMVP		0.73

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

Other links and lift over

dbSNP: rs145525174; hg19: chr1-94528774;