19-49830891-G-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_030973.4(MED25):c.1101+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,602,452 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 4 hom. )
Consequence
MED25
NM_030973.4 splice_donor_region, intron
NM_030973.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001785
2
Clinical Significance
Conservation
PhyloP100: 0.113
Genes affected
MED25 (HGNC:28845): (mediator complex subunit 25) This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000112 (163/1451302) while in subpopulation MID AF= 0.0054 (30/5558). AF 95% confidence interval is 0.00388. There are 4 homozygotes in gnomad4_exome. There are 105 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.1101+4G>A | splice_donor_region_variant, intron_variant | ENST00000312865.10 | |||
MED25 | NM_001378355.1 | c.1101+4G>A | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.1101+4G>A | splice_donor_region_variant, intron_variant | 1 | NM_030973.4 |
Frequencies
GnomAD3 genomes AF: 0.000113 AC: 17AN: 151036Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000154 AC: 37AN: 240048Hom.: 0 AF XY: 0.000222 AC XY: 29AN XY: 130904
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GnomAD4 exome AF: 0.000112 AC: 163AN: 1451302Hom.: 4 Cov.: 33 AF XY: 0.000145 AC XY: 105AN XY: 722272
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GnomAD4 genome AF: 0.000112 AC: 17AN: 151150Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 73918
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2021 | The c.1101+4G>A intronic alteration consists of a G to A substitution 4 nucleotides after exon 9 of the MED25 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | This sequence change falls in intron 9 of the MED25 gene. It does not directly change the encoded amino acid sequence of the MED25 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs746210338, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MED25-related conditions. ClinVar contains an entry for this variant (Variation ID: 329881). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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