NM_201542.5:c.69G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_201542.5(MED8):c.69G>T(p.Lys23Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

MED8
NM_201542.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

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 links:

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

MED8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED8	NM_201542.5 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 2 of 7	ENST00000372457.9	NP_963836.2	Q96G25-1
MED8	NM_052877.5 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 2 of 8		NP_443109.2	Q96G25-2
MED8	NM_001001653.3 link	c.-181G>T		5_prime_UTR_variant	Exon 2 of 7		NP_001001653.1	Q96G25-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED8	ENST00000372457.9 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 2 of 7	2	NM_201542.5	ENSP00000361535.4	Q96G25-1
MED8	ENST00000372455.4 link	c.-181G>T		5_prime_UTR_variant	Exon 2 of 7	1		ENSP00000361533.4	Q96G25-3
MED8	ENST00000290663.10 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 2 of 8	5		ENSP00000290663.6	Q96G25-2
MED8-AS1	ENST00000436713.1 link	n.282-340C>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248950

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461400

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.69G>T (p.K23N) alteration is located in exon 2 (coding exon 2) of the MED8 gene. This alteration results from a G to T substitution at nucleotide position 69, causing the lysine (K) at amino acid position 23 to be replaced by an asparagine (N). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.66

Loss of ubiquitination at K23 (P = 0.0174);Loss of ubiquitination at K23 (P = 0.0174);

MVP

0.65

MPC

1.1

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.81

gMVP

0.81

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over