rs104893946

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000369816.5(ELOVL4):​c.810C>G​(p.Tyr270Ter) variant causes a stop gained change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y270Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ELOVL4
ENST00000369816.5 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.63
Variant links:
Genes affected
ELOVL4 (HGNC:14415): (ELOVL fatty acid elongase 4) This gene encodes a membrane-bound protein which is a member of the ELO family, proteins which participate in the biosynthesis of fatty acids. Consistent with the expression of the encoded protein in photoreceptor cells of the retina, mutations and small deletions in this gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.143 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-79916743-G-C is Pathogenic according to our data. Variant chr6-79916743-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-79916743-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ELOVL4NM_022726.4 linkuse as main transcriptc.810C>G p.Tyr270Ter stop_gained 6/6 ENST00000369816.5 NP_073563.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ELOVL4ENST00000369816.5 linkuse as main transcriptc.810C>G p.Tyr270Ter stop_gained 6/61 NM_022726.4 ENSP00000358831 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Stargardt disease 3 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2004- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Molecular Genetics, University of ZurichJan 30, 2021- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 16, 2023This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4941). This premature translational stop signal has been observed in individual(s) with clinical features of Stargardt-like macular degeneration (PMID: 15557430, 27116512, 34073554). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Tyr270*) in the ELOVL4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the ELOVL4 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A
Vest4
0.84
GERP RS
6.0

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.

Other links and lift over

dbSNP: rs104893946; hg19: chr6-80626460; API