Genetic Variant MED9:p.Pro81Leu (chr17-17491296-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018019.3(MED9):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MED9
NM_018019.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08143172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED9	NM_018019.3 link	c.242C>T	p.Pro81Leu	missense_variant	Exon 2 of 2	ENST00000268711.4	NP_060489.1	Q9NWA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED9	ENST00000268711.4 link	c.242C>T	p.Pro81Leu	missense_variant	Exon 2 of 2	1	NM_018019.3	ENSP00000268711.3	Q9NWA0
MED9	ENST00000581315.1 link	n.*127C>T		non_coding_transcript_exon_variant	Exon 3 of 3	4		ENSP00000462204.1	J3KTK5
MED9	ENST00000581315.1 link	n.*127C>T		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000462204.1	J3KTK5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152106

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:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250846

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74292

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:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000355

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242C>T (p.P81L) alteration is located in exon 2 (coding exon 2) of the MED9 gene. This alteration results from a C to T substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by a leucine (L). 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

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.090

Eigen

Benign

0.18

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0050

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Benign

0.062

Sift

Benign

0.038

Sift4G

Benign

0.55

Polyphen

0.92

Vest4

0.15

MutPred

0.45

Loss of helix (P = 0.0237);

MVP

0.39

MPC

1.4

ClinPred

0.23

GERP RS

3.7

Varity_R

0.043

gMVP

0.24

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