6-131587823-T-G

Variant names:

• chr6-131587823-T-G
• NM_004830.4:c.3963A>C
• MED23 p.Leu1321Phe

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004830.4(MED23):​c.3963A>C​(p.Leu1321Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED23 NM_004830.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.766
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 autosomal recessive non-syndromic intellectual disability, intellectual disability, autosomal recessive 18, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21981624).

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.3963A>C	p.Leu1321Phe	missense	Exon 29 of 29	NP_004821.2
	MED23	NM_001376517.1		c.3981A>C	p.Leu1327Phe	missense	Exon 30 of 30	NP_001363446.1
	MED23	NM_015979.4		c.3981A>C	p.Leu1327Phe	missense	Exon 30 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.3963A>C	p.Leu1321Phe	missense	Exon 29 of 29	ENSP00000357047.3	Q9ULK4-1
	MED23	ENST00000354577.8	TSL:1	c.3981A>C	p.Leu1327Phe	missense	Exon 30 of 31	ENSP00000346588.4	Q9ULK4-3
	MED23	ENST00000368060.7	TSL:1	c.3963A>C	p.Leu1321Phe	missense	Exon 29 of 30	ENSP00000357039.3	Q9ULK4-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.085
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.77
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.46
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Varity_R		0.33
gMVP		0.64
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-131908963;