NM_004229.4:c.2761A>G

Variant names:

• chrX-40679983-T-C
• rs1456473588
• NM_004229.4:c.2761A>G

Variant summary

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

The NM_004229.4(MED14):​c.2761A>G​(p.Met921Val) 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: 23)
• Consequence: MED14 NM_004229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• 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.2761A>G	p.Met921Val	missense	Exon 21 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.2761A>G	p.Met921Val	missense	Exon 21 of 31	ENSP00000323720.1	O60244
	MED14	ENST00000918215.1		c.2761A>G	p.Met921Val	missense	Exon 21 of 33	ENSP00000588274.1
	MED14	ENST00000883181.1		c.2761A>G	p.Met921Val	missense	Exon 21 of 32	ENSP00000553240.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Benign	0.55
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.76	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.23
Sift	Benign	0.93	T
Sift4G	Benign	0.071	T
Polyphen		0.55	P
Vest4		0.77
MutPred		0.68		Loss of loop (P = 0.0374)
MVP		0.97
MPC		0.94
ClinPred		0.60	D
GERP RS		6.2
Varity_R		0.48
gMVP		0.78
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1456473588; hg19: chrX-40539235;