X-40654533-C-T

Variant names:

• chrX-40654533-C-T
• rs141642845
• NM_004229.4:c.4122G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_004229.4(MED14):​c.4122G>A​(p.Ser1374Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,208,461 control chromosomes in the GnomAD database, including 43 homozygotes. There are 2,789 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., 228 hem., cov: 23)
  • Exomes 𝑓: 0.0075 (39 hom. 2561 hem.)
• Consequence: MED14 NM_004229.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.390
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-40654533-C-T is Benign according to our data. Variant chrX-40654533-C-T is described in ClinVar as Benign. ClinVar VariationId is 777316.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 gene

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.4122G>A	p.Ser1374Ser	synonymous	Exon 30 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.4122G>A	p.Ser1374Ser	synonymous	Exon 30 of 31	ENSP00000323720.1	O60244
	MED14	ENST00000433003.1	TSL:1	c.819G>A	p.Ser273Ser	synonymous	Exon 6 of 6	ENSP00000411357.1	H7C3E5
	MED14	ENST00000918215.1		c.4302G>A	p.Ser1434Ser	synonymous	Exon 32 of 33	ENSP00000588274.1

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 688 AN: 110763 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.000953

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00915

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000380

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00686

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00658 AC: 1206 AN: 183262 AF XY: 0.00634

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00795

GnomAD4 exome AF: 0.00752 AC: 8254 AN: 1097643 Hom.: 39 Cov.: 30 AF XY: 0.00705 AC XY: 2561 AN XY: 363045

African (AFR) AF: 0.00106 AC: 28 AN: 26395

American (AMR) AF: 0.00216 AC: 76 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 266 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.000499 AC: 27 AN: 54108

European-Finnish (FIN) AF: 0.0269 AC: 1092 AN: 40524

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4115

European-Non Finnish (NFE) AF: 0.00769 AC: 6475 AN: 841650

Other (OTH) AF: 0.00627 AC: 289 AN: 46078

GnomAD4 genome AF: 0.00620 AC: 687 AN: 110818 Hom.: 4 Cov.: 23 AF XY: 0.00688 AC XY: 228 AN XY: 33150

African (AFR) AF: 0.000951 AC: 29 AN: 30497

American (AMR) AF: 0.00914 AC: 95 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 34 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.0278 AC: 161 AN: 5786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00686 AC: 363 AN: 52918

Other (OTH) AF: 0.00330 AC: 5 AN: 1516

Alfa AF: 0.00572 Hom.: 37

Bravo AF: 0.00544

EpiCase AF: 0.00671

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.6
DANN	Benign	0.57
PhyloP100		-0.39
Mutation Taster		=89/11	polymorphism (auto)

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: rs141642845; hg19: chrX-40513785;