NM_133640.5:c.85A>G

Variant summary

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

The NM_133640.5(MED22):​c.85A>G​(p.Ile29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MED22
NM_133640.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19
Variant links:
Genes affected
MED22 (HGNC:11477): (mediator complex subunit 22) This gene encodes a protein component of the mediator complex, which functions in the regulation of transcription by bridging interactions between gene-specific regulatory factors, RNA polymerase II, and general transcription factors. Alternatively spliced transcript variants encoding different isoforms have been observed. [provided by RefSeq, Jul 2013]

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=0.16317707).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED22NM_133640.5 linkc.85A>G p.Ile29Val missense_variant Exon 2 of 5 ENST00000343730.10 NP_598395.1 Q15528-1A0A024R8C5
MED22NM_181491.3 linkc.85A>G p.Ile29Val missense_variant Exon 2 of 4 NP_852468.1 Q15528-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED22ENST00000343730.10 linkc.85A>G p.Ile29Val missense_variant Exon 2 of 5 1 NM_133640.5 ENSP00000342343.5 Q15528-1
MED22ENST00000614493.4 linkc.85A>G p.Ile29Val missense_variant Exon 2 of 4 2 ENSP00000481493.1 Q15528-2
MED22ENST00000494177.6 linkc.85A>G p.Ile29Val missense_variant Exon 2 of 4 4 ENSP00000420815.1 E7EN96

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250802
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135638
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460832
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726780
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.85A>G (p.I29V) alteration is located in exon 2 (coding exon 1) of the MED22 gene. This alteration results from a A to G substitution at nucleotide position 85, causing the isoleucine (I) at amino acid position 29 to be replaced by a valine (V). 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
0.091
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.053
T;T;.;.;T;T;.;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.84
.;T;.;T;T;T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L;L;L;L;.;.;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.60
.;N;.;.;N;N;N;N
REVEL
Benign
0.052
Sift
Benign
0.10
.;T;.;.;T;T;T;T
Sift4G
Benign
0.14
T;T;T;T;T;.;T;T
Polyphen
0.016
B;B;B;B;.;.;.;.
Vest4
0.061
MutPred
0.56
Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);Gain of ubiquitination at K27 (P = 0.0898);
MVP
0.25
ClinPred
0.11
T
GERP RS
2.6
Varity_R
0.10
gMVP
0.80

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.

Other links and lift over

dbSNP: rs1253645444; hg19: chr9-136213433; API