1-94024977-C-T

Position:

chr1-94024977-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_ModerateBP6BP7BS2_Supporting

The NM_000350.3(ABCA4):c.4611G>A(p.Thr1537Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,614,132 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1537T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00094 ( 4 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -2.14

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:

ABCA4 (HGNC:):

ABCA4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 1-94024977-C-T is Benign according to our data. Variant chr1-94024977-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=2}. Variant chr1-94024977-C-T is described in Lovd as [Benign]. Variant chr1-94024977-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.14 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.4611G>A	p.Thr1537Thr	synonymous_variant	31/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.4389G>A	p.Thr1463Thr	synonymous_variant	30/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.4611G>A	p.Thr1537Thr	synonymous_variant	31/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000460514.1 linkuse as main transcript	n.105G>A		non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00112

AC:

281

AN:

251474

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000939

AC:

1372

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000947

AC XY:

689

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00365

Gnomad4 NFE exome

AF:

0.000962

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000978

AC:

149

AN:

152318

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000601

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ABCA4: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -

Retinal dystrophy

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -

ABCA4-related disorder

Uncertain: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

6.5

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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