chrX-40682647-G-A

Variant names:

• chrX-40682647-G-A
• NM_004229.4:c.2321C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004229.4(MED14):​c.2321C>T​(p.Ala774Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000369 in 1,082,728 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: MED14 NM_004229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34466165).

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.2321C>T	p.Ala774Val	missense	Exon 18 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.2321C>T	p.Ala774Val	missense	Exon 18 of 31	ENSP00000323720.1	O60244
	MED14	ENST00000918215.1		c.2321C>T	p.Ala774Val	missense	Exon 18 of 33	ENSP00000588274.1
	MED14	ENST00000883181.1		c.2321C>T	p.Ala774Val	missense	Exon 18 of 32	ENSP00000553240.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000369 AC: 4 AN: 1082728 Hom.: 0 Cov.: 29 AF XY: 0.00000284 AC XY: 1 AN XY: 352658

African (AFR) AF: 0.00 AC: 0 AN: 25697

American (AMR) AF: 0.00 AC: 0 AN: 34140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19214

East Asian (EAS) AF: 0.00 AC: 0 AN: 29146

South Asian (SAS) AF: 0.00 AC: 0 AN: 52202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00000480 AC: 4 AN: 832860

Other (OTH) AF: 0.00 AC: 0 AN: 45448

GnomAD4 genome Cov.: 22

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	0.30
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.44
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Uncertain	0.010	D
Polyphen		0.42	B
Vest4		0.51
MutPred		0.22		Gain of MoRF binding (P = 0.2433)
MVP		0.66
MPC		1.3
ClinPred		0.90	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.57
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chrX-40541899;