6-131621897-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_004830.4(MED23):​c.479T>C​(p.Leu160Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MED23
NM_004830.4 missense

Scores

10
7
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • intellectual disability, autosomal recessive 18
    Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • syndromic intellectual disability
    Inheritance: AR Classification: MODERATE Submitted by: ClinGen
  • autosomal recessive non-syndromic intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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 intellectual disability, autosomal recessive 18, syndromic intellectual disability, autosomal recessive non-syndromic intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.93
PP5
Variant 6-131621897-A-G is Pathogenic according to our data. Variant chr6-131621897-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191215.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED23NM_004830.4 linkc.479T>C p.Leu160Pro missense_variant Exon 6 of 29 ENST00000368068.8 NP_004821.2 Q9ULK4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED23ENST00000368068.8 linkc.479T>C p.Leu160Pro missense_variant Exon 6 of 29 1 NM_004830.4 ENSP00000357047.3 Q9ULK4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000101
Hom.:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
-
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Likely pathogenic
Review Status:flagged submission
Collection Method:research

- -

Intellectual disability, autosomal recessive 18 Pathogenic:1
Mar 17, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
.;D;.;.;.;.
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.81
L;L;L;.;L;L
PhyloP100
9.3
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-4.2
D;D;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;D;.
Vest4
0.96
MutPred
0.76
Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);
MVP
0.80
MPC
0.81
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.96
Mutation Taster
=0/100
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205583; hg19: chr6-131943037; API