1-43386881-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_201542.5(MED8):​c.388C>T​(p.Arg130Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MED8
NM_201542.5 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54
Variant links:
Genes affected
MED8 (HGNC:19971): (mediator complex subunit 8) This gene encodes a protein component of the mediator complex, which aids in transcriptional activation through interaction with RNA polymerase II and gene-specific transcription factors. The encoded protein may also function in ubiquitin ligation and protein degradation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]
MED8-AS1 (HGNC:40908): (MED8 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MED8NM_201542.5 linkc.388C>T p.Arg130Cys missense_variant 4/7 ENST00000372457.9 NP_963836.2 Q96G25-1
MED8NM_052877.5 linkc.388C>T p.Arg130Cys missense_variant 4/8 NP_443109.2 Q96G25-2
MED8NM_001001653.3 linkc.121C>T p.Arg41Cys missense_variant 4/7 NP_001001653.1 Q96G25-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MED8ENST00000372457.9 linkc.388C>T p.Arg130Cys missense_variant 4/72 NM_201542.5 ENSP00000361535.4 Q96G25-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250818
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461694
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2024The c.388C>T (p.R130C) alteration is located in exon 4 (coding exon 4) of the MED8 gene. This alteration results from a C to T substitution at nucleotide position 388, causing the arginine (R) at amino acid position 130 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
.;T;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.0094
T
MetaRNN
Uncertain
0.50
T;T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.7
L;L;.
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-2.5
N;N;D
REVEL
Benign
0.22
Sift
Uncertain
0.026
D;D;D
Sift4G
Uncertain
0.021
D;D;D
Polyphen
1.0
D;B;.
Vest4
0.59
MVP
0.49
MPC
0.43
ClinPred
0.77
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.28
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1185042517; hg19: chr1-43852552; COSMIC: COSV51942743; COSMIC: COSV51942743; API