rs559155109
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001371596.2(MFSD8):c.1361T>C(p.Met454Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 1 hom. )
Consequence
MFSD8
NM_001371596.2 missense
NM_001371596.2 missense
Scores
4
8
2
Clinical Significance
Conservation
PhyloP100: 8.40
Genes affected
MFSD8 (HGNC:28486): (major facilitator superfamily domain containing 8) This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.849
PP5
?
Variant 4-127920826-A-G is Pathogenic according to our data. Variant chr4-127920826-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127920826-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.1361T>C | p.Met454Thr | missense_variant | 12/12 | ENST00000641686.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFSD8 | ENST00000641686.2 | c.1361T>C | p.Met454Thr | missense_variant | 12/12 | NM_001371596.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 250440Hom.: 1 AF XY: 0.000140 AC XY: 19AN XY: 135464
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461588Hom.: 1 Cov.: 30 AF XY: 0.0000660 AC XY: 48AN XY: 727066
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2023 | Reported with a second variant, phase unknown, in an individual with retinal disease (Abdollahi et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 28041643, 28586915, 25333361, 31006324, 32037395, 35457110, 32581362) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 10, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2022 | The p.M454T variant (also known as c.1361T>C), located in coding exon 12 of the MFSD8 gene, results from a T to C substitution at nucleotide position 1361. The methionine at codon 454 is replaced by threonine, an amino acid with similar properties. This variant has been identified in the homozygous state and in trans with a MFSD8 likely pathogenic variant in multiple individuals with clinical features of MFSD8-associated disease (Patiño LC et al. PLoS One, 2014 Oct;9:e109576; Khan KN et al. Invest Ophthalmol Vis Sci, 2017 06;58:2906-2914; Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145; Zampaglione E et al. Genet Med, 2020 06;22:1079-1087; Carss KJ et al. Am J Hum Genet, 2017 01;100:75-90). In addition, this alteration has been shown to co-segregate with disease in multiple individuals from two families who have clinical features consistent with MFSD8-related disorders (Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Macular dystrophy with central cone involvement Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Neuronal ceroid lipofuscinosis 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 454 of the MFSD8 protein (p.Met454Thr). This variant is present in population databases (rs559155109, gnomAD 0.08%). This missense change has been observed in individuals with retinal dystrophy and neuronal ceroid lipofuscinosis (PMID: 25333361, 28041643, 28586915). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418295). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFSD8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2021 | Variant summary: MFSD8 c.1361T>C (p.Met454Thr) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250440 control chromosomes, predominantly at a frequency of 0.00082 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00082 vs 0.00094), allowing no conclusion about variant significance. c.1361T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with retinal disease (e.g. Carss_2017, Khan_2017, Zare-Abdollahi_2019). It was also reported in cis with another variant in homozygous siblings affected with late-infantile Neuronal Ceroid-Lipofuscinosis (Patino_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while two other submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;D;.;.;.;.;.;.;.
Vest4
0.89
MVP
0.82
MPC
0.53
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at