rs61753057

chr1-94080596-G-Achr1-94080596-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000350.3(ABCA4):c.981C>T(p.Pro327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,613,902 control chromosomes in the GnomAD database, including 1 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 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6 O:1
• Conservation: PhyloP100: -0.692

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-94080596-G-A is Benign according to our data. Variant chr1-94080596-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99516.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, not_provided=1, Likely_benign=3}. Variant chr1-94080596-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.692 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.981C>T	p.Pro327=	synonymous_variant	8/50	ENST00000370225.4
LOC124904222	XR_007066231.1	n.203-3133G>A		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1	c.981C>T	p.Pro327=	synonymous_variant	8/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.981C>T	p.Pro327=	synonymous_variant	8/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.981C>T	p.Pro327=	synonymous_variant	8/19

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251040 Hom.: 1 AF XY: 0.000487 AC XY: 66 AN XY: 135656

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000678 AC: 991 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.000657 AC XY: 478 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 34 AN XY: 74254

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.000434

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

ABCA4-related disorder Uncertain:1 Benign:1

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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 12, 2019	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2016

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 23, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.0
Dann	Benign	0.55

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: rs61753057; hg19: chr1-94546152; COSMIC: COSV64672588;