NM_004830.4:c.4080G>T

Variant names:

• chr6-131587706-C-A
• rs138742804
• NM_004830.4:c.4080G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_004830.4(MED23):​c.4080G>T​(p.Val1360Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,614,116 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: MED23 NM_004830.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.89
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 6-131587706-C-A is Benign according to our data. Variant chr6-131587706-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432201.
• BP7: Synonymous conserved (PhyloP=1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00338 (515/152300) while in subpopulation AFR AF = 0.0119 (495/41572). AF 95% confidence interval is 0.011. There are 4 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.4080G>T	p.Val1360Val	synonymous	Exon 29 of 29	NP_004821.2
	MED23	NM_001376517.1		c.4098G>T	p.Val1366Val	synonymous	Exon 30 of 30	NP_001363446.1
	MED23	NM_001376518.1		c.4026G>T	p.Val1342Val	synonymous	Exon 30 of 30	NP_001363447.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED23	ENST00000368068.8	TSL:1 MANE Select	c.4080G>T	p.Val1360Val	synonymous	Exon 29 of 29	ENSP00000357047.3	Q9ULK4-1
	MED23	ENST00000354577.8	TSL:1	c.4095+3G>T		splice_region intron	N/A	ENSP00000346588.4	Q9ULK4-3
	MED23	ENST00000368060.7	TSL:1	c.4077+3G>T		splice_region intron	N/A	ENSP00000357039.3	Q9ULK4-5

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000892 AC: 224 AN: 250986 AF XY: 0.000723

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000361 AC: 527 AN: 1461816 Hom.: 1 Cov.: 32 AF XY: 0.000341 AC XY: 248 AN XY: 727208

African (AFR) AF: 0.0133 AC: 445 AN: 33476

American (AMR) AF: 0.000425 AC: 19 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111968

Other (OTH) AF: 0.000712 AC: 43 AN: 60390

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74470

African (AFR) AF: 0.0119 AC: 495 AN: 41572

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00400

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, autosomal recessive 18 (1)
-	-	1	MED23-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.3
DANN	Benign	0.93
PhyloP100		1.9
Mutation Taster		=11/89	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: rs138742804; hg19: chr6-131908846;