X-40666738-T-C

Variant names:

• chrX-40666738-T-C
• rs751983140
• NM_004229.4:c.3247A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004229.4(MED14):​c.3247A>G​(p.Ser1083Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,207,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: MED14 NM_004229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16129789).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED14	NM_004229.4	c.3247A>G	p.Ser1083Gly	missense_variant	Exon 24 of 31	ENST00000324817.6	NP_004220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED14	ENST00000324817.6	c.3247A>G	p.Ser1083Gly	missense_variant	Exon 24 of 31	1	NM_004229.4	ENSP00000323720.1

Frequencies

GnomAD3 genomes AF: 0.0000711 AC: 8 AN: 112522 Hom.: 0 Cov.: 23 AF XY: 0.000115 AC XY: 4 AN XY: 34656

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000469

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: 0.0000188

Gnomad OTH AF: 0.000658

GnomAD3 exomes AF: 0.0000447 AC: 8 AN: 178837 Hom.: 0 AF XY: 0.0000314 AC XY: 2 AN XY: 63629

Gnomad AFR exome AF: 0.0000774

Gnomad AMR exome AF: 0.000221

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: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 9 AN: 1095192 Hom.: 0 Cov.: 29 AF XY: 0.00000831 AC XY: 3 AN XY: 361080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000228

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000711 AC: 8 AN: 112522 Hom.: 0 Cov.: 23 AF XY: 0.000115 AC XY: 4 AN XY: 34656

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.000469

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000658

Bravo AF: 0.000204

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3247A>G (p.S1083G) alteration is located in exon 24 (coding exon 24) of the MED14 gene. This alteration results from a A to G substitution at nucleotide position 3247, causing the serine (S) at amino acid position 1083 to be replaced by a glycine (G). 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	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.25	T
Sift4G	Benign	0.38	T
Polyphen		0.018	B
Vest4		0.32
MutPred		0.17		Loss of glycosylation at S1083 (P = 0.0361);
MVP		0.56
MPC		0.85
ClinPred		0.077	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.11

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

Other links and lift over

dbSNP: rs751983140; hg19: chrX-40525990;