chr6-41916806-C-T

Variant names:

• chr6-41916806-C-T
• rs140526856
• NM_004275.5:c.148G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004275.5(MED20):​c.148G>A​(p.Ala50Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: MED20 NM_004275.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02
• Publications: 9 publications found

Genes affected

MED20 (HGNC:16840): (mediator complex subunit 20) This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. A mutation in this gene has been associated with a novel infantile-onset neurodegenerative movement disorder. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

ENSG00000288721 (HGNC:):

BYSL (HGNC:1157): (bystin like) Bystin is expressed as a 2-kb major transcript and a 3.6-kb minor transcript in SNG-M cells and in human trophoblastic teratocarcinoma HT-H cells. Protein binding assays determined that bystin binds directly to trophinin and tastin, and that binding is enhanced when cytokeratins 8 and 18 are present. Immunocytochemistry of HT-H cells showed that bystin colocalizes with trophinin, tastin, and the cytokeratins, suggesting that these molecules form a complex in trophectoderm cells at the time of implantation. Using immunohistochemistry it was determined that trophinin and bystin are found in the placenta from the sixth week of pregnancy. Both proteins were localized in the cytoplasm of the syncytiotrophoblast in the chorionic villi and in endometrial decidual cells at the uteroplacental interface. After week 10, the levels of trophinin, tastin, and bystin decreased and then disappeared from placental villi. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025152504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004275.5. 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
	MED20	NM_004275.5	MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 2 of 4	NP_004266.2
	MED20	NM_001305457.2		c.148G>A	p.Ala50Thr	missense	Exon 2 of 4	NP_001292386.1	Q9H944-2
	MED20	NM_001305456.2		c.-155G>A		5_prime_UTR	Exon 2 of 5	NP_001292385.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED20	ENST00000265350.9	TSL:1 MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 2 of 4	ENSP00000265350.4	Q9H944-1
	ENSG00000288721	ENST00000684631.1		n.148G>A		non_coding_transcript_exon	Exon 2 of 10	ENSP00000507261.1
	MED20	ENST00000953440.1		c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	ENSP00000623499.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000656 AC: 165 AN: 251462 AF XY: 0.000625

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461772 Hom.: 0 Cov.: 30 AF XY: 0.00112 AC XY: 814 AN XY: 727188

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00144 AC: 1600 AN: 1111926

Other (OTH) AF: 0.000563 AC: 34 AN: 60386

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74448

African (AFR) AF: 0.000626 AC: 26 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.000608

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

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	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.067
Sift	Benign	0.41	T
Sift4G	Benign	0.32	T
Polyphen		0.21	B
Vest4		0.21
MVP		0.16
MPC		0.37
ClinPred		0.0087	T
GERP RS		3.6
Varity_R		0.10
gMVP		0.34
Mutation Taster		=79/21	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: rs140526856; hg19: chr6-41884544; COSMIC: COSV54826320; COSMIC: COSV54826320;