X-40659464-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004229.4(MED14):​c.3828T>A​(p.Asp1276Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,209,844 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., 14 hem., cov: 23)
Exomes 𝑓: 0.000051 ( 0 hom. 15 hem. )

Consequence

MED14
NM_004229.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011220068).
BS2
High Hemizygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED14NM_004229.4 linkc.3828T>A p.Asp1276Glu missense_variant Exon 27 of 31 ENST00000324817.6 NP_004220.2 O60244

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED14ENST00000324817.6 linkc.3828T>A p.Asp1276Glu missense_variant Exon 27 of 31 1 NM_004229.4 ENSP00000323720.1 O60244
MED14ENST00000433003.1 linkc.525T>A p.Asp175Glu missense_variant Exon 3 of 6 1 ENSP00000411357.1 H7C3E5
MED14ENST00000472736.1 linkn.356T>A non_coding_transcript_exon_variant Exon 1 of 2 5
MED14ENST00000416199.5 linkc.-130T>A upstream_gene_variant 2 ENSP00000392586.1 H7C017

Frequencies

GnomAD3 genomes
AF:
0.000408
AC:
46
AN:
112608
Hom.:
0
Cov.:
23
AF XY:
0.000403
AC XY:
14
AN XY:
34750
show subpopulations
Gnomad AFR
AF:
0.00142
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000939
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:
0.0000187
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
21
AN:
180914
Hom.:
0
AF XY:
0.0000611
AC XY:
4
AN XY:
65496
show subpopulations
Gnomad AFR exome
AF:
0.00160
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000510
AC:
56
AN:
1097181
Hom.:
0
Cov.:
29
AF XY:
0.0000414
AC XY:
15
AN XY:
362619
show subpopulations
Gnomad4 AFR exome
AF:
0.00205
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:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.000408
AC:
46
AN:
112663
Hom.:
0
Cov.:
23
AF XY:
0.000402
AC XY:
14
AN XY:
34815
show subpopulations
Gnomad4 AFR
AF:
0.00142
Gnomad4 AMR
AF:
0.0000937
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000187
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000304
Hom.:
2
Bravo
AF:
0.000423
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000577
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3828T>A (p.D1276E) alteration is located in exon 27 (coding exon 27) of the MED14 gene. This alteration results from a T to A substitution at nucleotide position 3828, causing the aspartic acid (D) at amino acid position 1276 to be replaced by a glutamic acid (E). 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
0.056
BayesDel_addAF
Benign
-0.76
T
BayesDel_noAF
Benign
-0.88
CADD
Benign
12
DANN
Benign
0.84
DEOGEN2
Benign
0.12
T;T
FATHMM_MKL
Benign
0.76
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.3
N;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.44
N;N
REVEL
Benign
0.16
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;.
Vest4
0.084
MutPred
0.36
Gain of disorder (P = 0.0607);.;
MVP
0.37
MPC
0.87
ClinPred
0.027
T
GERP RS
1.4
Varity_R
0.10
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs147145468; hg19: chrX-40518716; API