9-132014366-AGC-CGT

Variant names:

• chr9-132014366-AGC-CGT
• NM_004269.4:c.448_450delGCTinsACG
• MED27 p.Ala150Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_004269.4(MED27):​c.448_450delGCTinsACG​(p.Ala150Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: MED27 NM_004269.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.07
• Publications: 0 publications found

Genes affected

MED27 (HGNC:2377): (mediator complex subunit 27) 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. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Dec 2011]

MED27 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2645 (below the threshold of 3.09). Trascript score misZ: 1.7239 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, syndromic intellectual disability.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004269.4. 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
	MED27	NM_004269.4	MANE Select	c.448_450delGCTinsACG	p.Ala150Thr	missense	N/A	NP_004260.2
	MED27	NM_001253881.2		c.448_450delGCTinsACG	p.Ala150Thr	missense	N/A	NP_001240810.1	Q6P2C8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED27	ENST00000292035.10	TSL:1 MANE Select	c.448_450delGCTinsACG	p.Ala150Thr	missense	N/A	ENSP00000292035.5	Q6P2C8-1
	MED27	ENST00000357028.6	TSL:1	c.448_450delGCTinsACG	p.Ala150Thr	missense	N/A	ENSP00000349530.3	Q6P2C8-2
	MED27	ENST00000897372.1		c.448_450delGCTinsACG	p.Ala150Thr	missense	N/A	ENSP00000567431.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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: chr9-134889753;