rs150598354

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_004830.4(MED23):c.3860A>G(p.His1287Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

MED23
NM_004830.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

MED23 (HGNC:2372): (mediator complex subunit 23) 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 also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]

MED23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09958169).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000387 (59/152294) while in subpopulation NFE AF= 0.000764 (52/68022). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED23	NM_004830.4 link	c.3860A>G	p.His1287Arg	missense_variant	Exon 28 of 29	ENST00000368068.8	NP_004821.2	Q9ULK4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED23	ENST00000368068.8 link	c.3860A>G	p.His1287Arg	missense_variant	Exon 28 of 29	1	NM_004830.4	ENSP00000357047.3		Q9ULK4-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000764

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000426

AC:

107

AN:

251206

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000828

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000560

AC:

818

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000568

AC XY:

413

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000689

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000387

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000718

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jun 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MED23 c.3878A>G (p.His1293Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251206 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MED23 causing Mental Retardation, Autosomal Recessive 18, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3878A>G in individuals affected with Mental Retardation, Autosomal Recessive 18 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 211488). Based on the evidence outlined above, the variant was classified as uncertain significance. -

May 23, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3878A>G (p.H1293R) alteration is located in exon 29 (coding exon 29) of the MED23 gene. This alteration results from a A to G substitution at nucleotide position 3878, causing the histidine (H) at amino acid position 1293 to be replaced by an arginine (R). 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

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.30

.;T;.;.

Eigen

Benign

0.071

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.55

.;N;N;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.56

P;P;.;.

Vest4

0.60

MVP

0.81

MPC

1.3

ClinPred

0.042

GERP RS

5.2

Varity_R

0.28

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over