Variant chr1-43388362-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_201542.5(MED8):c.73T>C(p.Ser25Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MED8
NM_201542.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.70

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED8	NM_201542.5 link	c.73T>C	p.Ser25Pro	missense_variant	2/7	ENST00000372457.9	NP_963836.2	Q96G25-1
MED8	NM_052877.5 link	c.73T>C	p.Ser25Pro	missense_variant	2/8		NP_443109.2	Q96G25-2
MED8	NM_001001653.3 link	c.-177T>C		5_prime_UTR_variant	2/7		NP_001001653.1	Q96G25-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MED8	ENST00000372457.9 link	c.73T>C	p.Ser25Pro	missense_variant	2/7	2	NM_201542.5	ENSP00000361535.4	Q96G25-1
MED8	ENST00000372455.4 link	c.-177T>C		5_prime_UTR_variant	2/7	1		ENSP00000361533.4	Q96G25-3
MED8	ENST00000290663.10 link	c.73T>C	p.Ser25Pro	missense_variant	2/8	5		ENSP00000290663.6	Q96G25-2
MED8-AS1	ENST00000436713.1 link	n.282-344A>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461402

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727020

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.73T>C (p.S25P) alteration is located in exon 2 (coding exon 2) of the MED8 gene. This alteration results from a T to C substitution at nucleotide position 73, causing the serine (S) at amino acid position 25 to be replaced by a proline (P). 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

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

-0.092

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.37

Loss of stability (P = 0.0942);Loss of stability (P = 0.0942);

MVP

0.68

MPC

1.1

ClinPred

0.98

GERP RS

5.8

Varity_R

0.86

gMVP

0.89

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over