9-131884070-T-A

Variant names:

• chr9-131884070-T-A
• rs142538381
• NM_004269.4:c.711A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004269.4(MED27):​c.711A>T​(p.Gln237His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED27 NM_004269.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED27	NM_004269.4	c.711A>T	p.Gln237His	missense_variant	Exon 6 of 8	ENST00000292035.10	NP_004260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED27	ENST00000292035.10	c.711A>T	p.Gln237His	missense_variant	Exon 6 of 8	1	NM_004269.4	ENSP00000292035.5
MED27	ENST00000357028.6	c.603A>T	p.Gln201His	missense_variant	Exon 5 of 7	1		ENSP00000349530.3
MED27	ENST00000651950.1	c.711A>T	p.Gln237His	missense_variant	Exon 6 of 9			ENSP00000498604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460038 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726242

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111158

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.711A>T (p.Q237H) alteration is located in exon 6 (coding exon 6) of the MED27 gene. This alteration results from a A to T substitution at nucleotide position 711, causing the glutamine (Q) at amino acid position 237 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.050	.;N
PhyloP100		-0.020
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	.;N
REVEL	Uncertain	0.31
Sift	Benign	0.051	.;T
Sift4G	Benign	0.062	T;T
Polyphen		0.99	D;D
Vest4		0.64
MutPred		0.63		.;Gain of loop (P = 0.1069);
MVP		0.50
MPC		1.3
ClinPred		0.98	D
GERP RS		-4.7
Varity_R		0.26
gMVP		0.64
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs142538381; hg19: chr9-134759457;