19-49832310-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_030973.4(MED25):​c.1377C>T​(p.Thr459Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,602,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T459T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

MED25
NM_030973.4 splice_region, synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.760
Variant links:
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]
MIR6800 (HGNC:50042): (microRNA 6800) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 19-49832310-C-T is Benign according to our data. Variant chr19-49832310-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49832310-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.76 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED25NM_030973.4 linkc.1377C>T p.Thr459Thr splice_region_variant, synonymous_variant Exon 13 of 18 ENST00000312865.10 NP_112235.2 Q71SY5-1
MED25NM_001378355.1 linkc.1377C>T p.Thr459Thr splice_region_variant, synonymous_variant Exon 13 of 18 NP_001365284.1
MIR6800NR_106858.1 linkn.*211C>T downstream_gene_variant
MIR6800unassigned_transcript_3297 n.*214C>T downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED25ENST00000312865.10 linkc.1377C>T p.Thr459Thr splice_region_variant, synonymous_variant Exon 13 of 18 1 NM_030973.4 ENSP00000326767.5 Q71SY5-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000884
AC:
21
AN:
237478
Hom.:
0
AF XY:
0.0000857
AC XY:
11
AN XY:
128324
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000197
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000174
AC:
253
AN:
1450388
Hom.:
0
Cov.:
31
AF XY:
0.000186
AC XY:
134
AN XY:
721008
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000569
Gnomad4 NFE exome
AF:
0.000221
Gnomad4 OTH exome
AF:
0.0000833
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000307
Hom.:
0
Bravo
AF:
0.000132

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Benign:1
Dec 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
13
DANN
Benign
0.84
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs374928221; hg19: chr19-50335567; API