NM_201542.5:c.388C>T

Variant names:

• chr1-43386881-G-A
• rs1185042517
• NM_201542.5:c.388C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_201542.5(MED8):​c.388C>T​(p.Arg130Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R130H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MED8 NM_201542.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• Publications: 3 publications found

Genes affected

MED8 (HGNC:19971): (mediator complex subunit 8) This gene encodes a protein component of the mediator complex, which aids in transcriptional activation through interaction with RNA polymerase II and gene-specific transcription factors. The encoded protein may also function in ubiquitin ligation and protein degradation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

MED8-AS1 (HGNC:40908): (MED8 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201542.5. 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
	MED8	NM_201542.5	MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 4 of 7	NP_963836.2	Q96G25-1
	MED8	NM_052877.5		c.388C>T	p.Arg130Cys	missense	Exon 4 of 8	NP_443109.2	Q96G25-2
	MED8	NM_001001653.3		c.121C>T	p.Arg41Cys	missense	Exon 4 of 7	NP_001001653.1	Q96G25-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED8	ENST00000372457.9	TSL:2 MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 4 of 7	ENSP00000361535.4	Q96G25-1
	MED8	ENST00000372455.4	TSL:1	c.121C>T	p.Arg41Cys	missense	Exon 4 of 7	ENSP00000361533.4	Q96G25-3
	MED8	ENST00000290663.10	TSL:5	c.388C>T	p.Arg130Cys	missense	Exon 4 of 8	ENSP00000290663.6	Q96G25-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250818 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.22
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.49
MPC		0.43
ClinPred		0.77	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.67
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1185042517; hg19: chr1-43852552; COSMIC: COSV51942743; COSMIC: COSV51942743;