NM_004229.4:c.4358G>C

Variant names:

• chrX-40651813-C-G
• rs756934224
• NM_004229.4:c.4358G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004229.4(MED14):​c.4358G>C​(p.Arg1453Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1453H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED14 NM_004229.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18327281).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004229.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED14	NM_004229.4	MANE Select	c.4358G>C	p.Arg1453Pro	missense	Exon 31 of 31	NP_004220.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED14	ENST00000324817.6	TSL:1 MANE Select	c.4358G>C	p.Arg1453Pro	missense	Exon 31 of 31	ENSP00000323720.1	O60244
	MED14	ENST00000918215.1		c.4538G>C	p.Arg1513Pro	missense	Exon 33 of 33	ENSP00000588274.1
	MED14	ENST00000883181.1		c.4451G>C	p.Arg1484Pro	missense	Exon 32 of 32	ENSP00000553240.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.61	P
Vest4		0.40
MutPred		0.33		Gain of glycosylation at R1453 (P = 0.0033)
MVP		0.51
MPC		2.0
ClinPred		0.74	D
GERP RS		4.1
Varity_R		0.49
gMVP		0.55
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs756934224; hg19: chrX-40511065;