Genetic Variant MED9:p.Pro67Leu (chr17-17477241-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018019.3(MED9):c.200C>T(p.Pro67Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,452,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MED9
NM_018019.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

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.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED9	NM_018019.3 link	c.200C>T	p.Pro67Leu	missense_variant	Exon 1 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.200C>T	p.Pro67Leu	missense_variant	Exon 1 of 2	1	NM_018019.3	ENSP00000268711.3	Q9NWA0
MED9	ENST00000580462.1 link	c.200C>T	p.Pro67Leu	missense_variant	Exon 1 of 2	1		ENSP00000463031.1	J3KTK5
MED9	ENST00000581315.1 link	n.200C>T		non_coding_transcript_exon_variant	Exon 1 of 3	4		ENSP00000462204.1	J3KTK5
MED9	ENST00000585041.1 link	n.236C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000454

AC:

AN:

242482

Hom.:

AF XY:

0.0000457

AC XY:

AN XY:

131372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.00

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:

0.0000131

AC:

AN:

1452252

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

721158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000547

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

Cov.:

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200C>T (p.P67L) alteration is located in exon 1 (coding exon 1) of the MED9 gene. This alteration results from a C to T substitution at nucleotide position 200, causing the proline (P) at amino acid position 67 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

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

D;.

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

-0.016

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-7.1

D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.12

T;D

Polyphen

1.0

D;.

Vest4

0.85

MutPred

0.56

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.44

MPC

1.7

ClinPred

0.94

GERP RS

5.7

Varity_R

0.79

gMVP

0.67

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

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