rs75039907
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001371596.2(MFSD8):c.1351-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,612,396 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0057 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00058 ( 13 hom. )
Consequence
MFSD8
NM_001371596.2 splice_polypyrimidine_tract, intron
NM_001371596.2 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00006743
2
Clinical Significance
Conservation
PhyloP100: 0.175
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 4-127920845-G-A is Benign according to our data. Variant chr4-127920845-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127920845-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00565 (860/152100) while in subpopulation AFR AF= 0.0201 (832/41480). AF 95% confidence interval is 0.0189. There are 11 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 11 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.1351-9C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000641686.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFSD8 | ENST00000641686.2 | c.1351-9C>T | splice_polypyrimidine_tract_variant, intron_variant | NM_001371596.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00565 AC: 859AN: 151982Hom.: 11 Cov.: 32
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GnomAD3 exomes AF: 0.00157 AC: 389AN: 247704Hom.: 7 AF XY: 0.00137 AC XY: 183AN XY: 134060
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GnomAD4 exome AF: 0.000578 AC: 844AN: 1460296Hom.: 13 Cov.: 30 AF XY: 0.000526 AC XY: 382AN XY: 726358
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 7 Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Nov 28, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 20, 2022 | - - |
Late-infantile neuronal ceroid lipofuscinosis Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Benign:1
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 20, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at