chrX-40654997-C-T

Variant names:

• chrX-40654997-C-T
• rs2146606969
• NM_004229.4:c.4036G>A

Variant summary

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

The NM_004229.4(MED14):​c.4036G>A​(p.Ala1346Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MED14 NM_004229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4036G>A	p.Ala1346Thr	missense	Exon 29 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.4036G>A	p.Ala1346Thr	missense	Exon 29 of 31	ENSP00000323720.1	O60244
	MED14	ENST00000433003.1	TSL:1	c.733G>A	p.Ala245Thr	missense	Exon 5 of 6	ENSP00000411357.1	H7C3E5
	MED14	ENST00000918215.1		c.4216G>A	p.Ala1406Thr	missense	Exon 31 of 33	ENSP00000588274.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.29		Gain of glycosylation at A1346 (P = 0.0017)
MVP		0.83
MPC		1.2
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.38
gMVP		0.81
Mutation Taster		=44/56	disease causing

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: rs2146606969; hg19: chrX-40514249; COSMIC: COSV61356388; COSMIC: COSV61356388;