rs6597536

Variant names:

• chr9-131916392-C-T
• rs6597536
• NM_004269.4:c.574-22400G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004269.4(MED27):​c.574-22400G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 152,222 control chromosomes in the GnomAD database, including 56,660 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56660 hom., cov: 32)
• Consequence: MED27 NM_004269.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.264
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

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.574-22400G>A		intron	N/A	NP_004260.2
	MED27	NM_001253881.2		c.573+22989G>A		intron	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.574-22400G>A		intron	N/A	ENSP00000292035.5	Q6P2C8-1
	MED27	ENST00000357028.6	TSL:1	c.573+22989G>A		intron	N/A	ENSP00000349530.3	Q6P2C8-2
	MED27	ENST00000897372.1		c.574-22400G>A		intron	N/A	ENSP00000567431.1

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131071 AN: 152104 Hom.: 56595 Cov.: 32

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.841

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

GnomAD4 genome AF: 0.862 AC: 131198 AN: 152222 Hom.: 56660 Cov.: 32 AF XY: 0.861 AC XY: 64079 AN XY: 74430

African (AFR) AF: 0.899 AC: 37306 AN: 41508

American (AMR) AF: 0.807 AC: 12349 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3145 AN: 3472

East Asian (EAS) AF: 0.725 AC: 3749 AN: 5168

South Asian (SAS) AF: 0.860 AC: 4149 AN: 4822

European-Finnish (FIN) AF: 0.870 AC: 9237 AN: 10612

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58450 AN: 68026

Other (OTH) AF: 0.840 AC: 1775 AN: 2112

Alfa AF: 0.860 Hom.: 93536

Bravo AF: 0.857

Asia WGS AF: 0.794 AC: 2762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs6597536; hg19: chr9-134791779;