chr9-131943122-T-C

Variant names:

• chr9-131943122-T-C
• rs4128956
• NM_004269.4:c.480-3648A>G

Variant summary

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

The NM_004269.4(MED27):​c.480-3648A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 152,036 control chromosomes in the GnomAD database, including 37,048 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 0.69 (37048 hom., cov: 31)
• Consequence: MED27 NM_004269.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.761
• Publications: 5 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=-0.57).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED27	NM_004269.4	c.480-3648A>G		intron_variant	Intron 3 of 7	ENST00000292035.10	NP_004260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED27	ENST00000292035.10	c.480-3648A>G		intron_variant	Intron 3 of 7	1	NM_004269.4	ENSP00000292035.5
MED27	ENST00000357028.6	c.480-3648A>G		intron_variant	Intron 3 of 6	1		ENSP00000349530.3
MED27	ENST00000651950.1	c.480-3648A>G		intron_variant	Intron 3 of 8			ENSP00000498604.1
MED27	ENST00000651555.1	c.480-3648A>G		intron_variant	Intron 3 of 3			ENSP00000498641.1

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105037 AN: 151918 Hom.: 36993 Cov.: 31

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.692 AC: 105151 AN: 152036 Hom.: 37048 Cov.: 31 AF XY: 0.692 AC XY: 51414 AN XY: 74316

African (AFR) AF: 0.822 AC: 34098 AN: 41478

American (AMR) AF: 0.732 AC: 11186 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1865 AN: 3464

East Asian (EAS) AF: 0.719 AC: 3708 AN: 5158

South Asian (SAS) AF: 0.749 AC: 3611 AN: 4818

European-Finnish (FIN) AF: 0.584 AC: 6166 AN: 10564

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42338 AN: 67966

Other (OTH) AF: 0.683 AC: 1442 AN: 2110

Alfa AF: 0.649 Hom.: 122619

Bravo AF: 0.711

Asia WGS AF: 0.741 AC: 2576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.76
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: rs4128956; hg19: chr9-134818509;