rs150598354

Variant names:

• chr6-131589544-T-C
• rs150598354
• NM_004830.4:c.3860A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.02
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 18

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.7291 (above the threshold of 3.09). Trascript score misZ: 5.9944 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal recessive 18, syndromic intellectual disability, autosomal recessive non-syndromic intellectual disability.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004830.4. 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
	MED23	NM_004830.4	MANE Select	c.3860A>G	p.His1287Arg	missense	Exon 28 of 29	NP_004821.2
	MED23	NM_001376517.1		c.3878A>G	p.His1293Arg	missense	Exon 29 of 30	NP_001363446.1
	MED23	NM_015979.4		c.3878A>G	p.His1293Arg	missense	Exon 29 of 31	NP_057063.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED23	ENST00000368068.8	TSL:1 MANE Select	c.3860A>G	p.His1287Arg	missense	Exon 28 of 29	ENSP00000357047.3	Q9ULK4-1
	MED23	ENST00000354577.8	TSL:1	c.3878A>G	p.His1293Arg	missense	Exon 29 of 31	ENSP00000346588.4	Q9ULK4-3
	MED23	ENST00000368060.7	TSL:1	c.3860A>G	p.His1287Arg	missense	Exon 28 of 30	ENSP00000357039.3	Q9ULK4-5

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152176 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000426 AC: 107 AN: 251206 AF XY: 0.000383

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 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.: 0 Cov.: 31 AF XY: 0.000568 AC XY: 413 AN XY: 727124

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000689 AC: 766 AN: 1111788

Other (OTH) AF: 0.000679 AC: 41 AN: 60376

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74476

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000689 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.071
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N
PhyloP100		8.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.43
Sift	Benign	0.18	T
Sift4G	Benign	0.42	T
Polyphen		0.56	P
Vest4		0.60
MVP		0.81
MPC		1.3
ClinPred		0.042	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.33
Mutation Taster		=28/72	disease causing

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: rs150598354; hg19: chr6-131910684;