Variant chr17-17477045-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_018019.3(MED9):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,453,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MED9
NM_018019.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.77

Variant links:

Genes affected

MED9 (HGNC:25487): (mediator complex subunit 9) The multiprotein Mediator complex is a coactivator required for activation of RNA polymerase II transcription by DNA bound transcription factors. The protein encoded by this gene is thought to be a subunit of the Mediator complex. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

MED9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity MED9_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2238523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED9	NM_018019.3 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant	1/2	ENST00000268711.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MED9	ENST00000268711.4 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant	1/2	1	NM_018019.3	P1
MED9	ENST00000580462.1 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant	1/2	1
MED9	ENST00000585041.1 linkuse as main transcript	n.40G>T		non_coding_transcript_exon_variant	1/1
MED9	ENST00000581315.1 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, NMD_transcript_variant	1/3	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000251

AC:

AN:

238808

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000335

Gnomad SAS 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:

0.00000688

AC:

AN:

1453528

Hom.:

Cov.:

AF XY:

0.00000968

AC XY:

AN XY:

723382

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000210

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000829

AC:

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

Feb 28, 2023

The c.4G>T (p.A2S) alteration is located in exon 1 (coding exon 1) of the MED9 gene. This alteration results from a G to T substitution at nucleotide position 4, causing the alanine (A) at amino acid position 2 to be replaced by a serine (S). 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

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.045

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.48

T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

0.90

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.040

N;.

REVEL

Benign

0.068

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.49

T;T

Polyphen

0.63

P;.

Vest4

0.39

MutPred

0.13

Gain of phosphorylation at A2 (P = 0.0207);Gain of phosphorylation at A2 (P = 0.0207);

MVP

0.39

MPC

0.65

ClinPred

0.40

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.22

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