X-40682946-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004229.4(MED14):​c.2108G>A​(p.Arg703His) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,208,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000070 ( 0 hom. 30 hem. )

Consequence

MED14
NM_004229.4 missense

Scores

2
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86
Variant links:
Genes affected
MED14 (HGNC:2370): (mediator complex subunit 14) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein contains a bipartite nuclear localization signal. This gene is known to escape chromosome X-inactivation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.22769323).
BS2
High Hemizygotes in GnomAdExome4 at 30 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED14NM_004229.4 linkc.2108G>A p.Arg703His missense_variant Exon 17 of 31 ENST00000324817.6 NP_004220.2 O60244

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED14ENST00000324817.6 linkc.2108G>A p.Arg703His missense_variant Exon 17 of 31 1 NM_004229.4 ENSP00000323720.1 O60244
MED14ENST00000496531.2 linkn.-33G>A upstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000626
AC:
7
AN:
111878
Hom.:
0
Cov.:
23
AF XY:
0.0000293
AC XY:
1
AN XY:
34080
show subpopulations
Gnomad AFR
AF:
0.0000325
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000365
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000940
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000494
AC:
9
AN:
182046
Hom.:
0
AF XY:
0.0000599
AC XY:
4
AN XY:
66732
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000212
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000370
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000702
AC:
77
AN:
1096271
Hom.:
0
Cov.:
30
AF XY:
0.0000829
AC XY:
30
AN XY:
361691
show subpopulations
Gnomad4 AFR exome
AF:
0.0000380
Gnomad4 AMR exome
AF:
0.0000571
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.000223
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000690
Gnomad4 OTH exome
AF:
0.0000652
GnomAD4 genome
AF:
0.0000626
AC:
7
AN:
111878
Hom.:
0
Cov.:
23
AF XY:
0.0000293
AC XY:
1
AN XY:
34080
show subpopulations
Gnomad4 AFR
AF:
0.0000325
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000365
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000940
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 12, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2108G>A (p.R703H) alteration is located in exon 17 (coding exon 17) of the MED14 gene. This alteration results from a G to A substitution at nucleotide position 2108, causing the arginine (R) at amino acid position 703 to be replaced by a histidine (H). 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
0.072
BayesDel_addAF
Benign
-0.090
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.32
T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.7
L
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.13
Sift
Uncertain
0.012
D
Sift4G
Uncertain
0.016
D
Polyphen
0.96
D
Vest4
0.19
MVP
0.58
MPC
1.7
ClinPred
0.18
T
GERP RS
5.8
Varity_R
0.46
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs765984652; hg19: chrX-40542198; API