NM_004269.4:c.523G>A

Variant names:

• chr9-131939431-C-T
• rs933842047
• NM_004269.4:c.523G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004269.4(MED27):​c.523G>A​(p.Glu175Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,184 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 0.000013 (0 hom., cov: 32)
• Consequence: MED27 NM_004269.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47
• Publications: 1 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37506202).

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.523G>A	p.Glu175Lys	missense	Exon 4 of 8	NP_004260.2
	MED27	NM_001253881.2		c.523G>A	p.Glu175Lys	missense	Exon 4 of 7	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.523G>A	p.Glu175Lys	missense	Exon 4 of 8	ENSP00000292035.5	Q6P2C8-1
	MED27	ENST00000357028.6	TSL:1	c.523G>A	p.Glu175Lys	missense	Exon 4 of 7	ENSP00000349530.3	Q6P2C8-2
	MED27	ENST00000897372.1		c.523G>A	p.Glu175Lys	missense	Exon 4 of 9	ENSP00000567431.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.5
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.027	D
Polyphen		0.027	B
Vest4		0.57
MutPred		0.52		Gain of MoRF binding (P = 0.0056)
MVP		0.53
MPC		0.68
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.44
gMVP		0.54
Mutation Taster		=69/31	polymorphism

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: rs933842047; hg19: chr9-134814818; COSMIC: COSV52601426;