4-127957540-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001371596.2(MFSD8):c.115A>T(p.Ile39Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,611,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I39V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001371596.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.115A>T | p.Ile39Phe | missense_variant | 2/12 | ENST00000641686.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFSD8 | ENST00000641686.2 | c.115A>T | p.Ile39Phe | missense_variant | 2/12 | NM_001371596.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 250794Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135634
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1459690Hom.: 0 Cov.: 29 AF XY: 0.0000275 AC XY: 20AN XY: 726284
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74364
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 24, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2021 | The c.115A>T (p.I39F) alteration is located in exon 3 (coding exon 2) of the MFSD8 gene. This alteration results from a A to T substitution at nucleotide position 115, causing the isoleucine (I) at amino acid position 39 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Late-infantile neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 31, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2016 | The I39F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I39F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Neuronal ceroid lipofuscinosis 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 39 of the MFSD8 protein (p.Ile39Phe). This variant is present in population databases (rs201739608, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 206167). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at