rs886044719

Variant names:

• chr1-94113047-A-C
• rs886044719
• NM_000350.3:c.86T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-94113047-A-C
• chr1-94113047-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000350.3(ABCA4):​c.86T>G​(p.Leu29Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L29F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.28

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 Pathogenic. Variant got 10 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, 3 uncertain in NM_000350.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94113048-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 1-94113047-A-C is Pathogenic according to our data. Variant chr1-94113047-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94113047-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.86T>G	p.Leu29Arg	missense_variant	Exon 2 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.86T>G	p.Leu29Arg	missense_variant	Exon 2 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.86T>G	p.Leu29Arg	missense_variant	Exon 2 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.86T>G	p.Leu29Arg	missense_variant	Exon 2 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Jan 01, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:1

Jan 01, 2010

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.4	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.62		Loss of catalytic residue at L29 (P = 0.0142);Loss of catalytic residue at L29 (P = 0.0142);
MVP		0.99
MPC		0.47
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.84
gMVP		0.94

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: rs886044719; hg19: chr1-94578603;