Genetic Variant MED22:p.Asp164His (chr9-133341618-C-G) – 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_133640.5(MED22):c.490G>C(p.Asp164His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,598,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MED22
NM_133640.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

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]

MED22 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=0.17087707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED22	NM_133640.5 link	c.490G>C	p.Asp164His	missense_variant	Exon 5 of 5	ENST00000343730.10	NP_598395.1	Q15528-1A0A024R8C5
MED22	NM_181491.3 link	c.*2497G>C		3_prime_UTR_variant	Exon 4 of 4		NP_852468.1	Q15528-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED22	ENST00000343730.10 link	c.490G>C	p.Asp164His	missense_variant	Exon 5 of 5	1	NM_133640.5	ENSP00000342343.5	Q15528-1
MED22	ENST00000610888 link	c.*2497G>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000478773.1	Q15528-2
MED22	ENST00000614493 link	c.*2497G>C		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000481493.1	Q15528-2
MED22	ENST00000610672.4 link	c.490G>C	p.Asp164His	missense_variant	Exon 5 of 5	2		ENSP00000482438.1	Q15528-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000426

AC:

AN:

234762

Hom.:

AF XY:

0.0000391

AC XY:

AN XY:

127800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1446696

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719616

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000785

Gnomad4 SAS exome

AF:

0.0000357

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000542

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.490G>C (p.D164H) alteration is located in exon 5 (coding exon 4) of the MED22 gene. This alteration results from a G to C substitution at nucleotide position 490, causing the aspartic acid (D) at amino acid position 164 to be replaced by a histidine (H). 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

0.096

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

T;T

Eigen

Benign

0.068

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.43

.;N

REVEL

Benign

0.14

Sift

Uncertain

0.0090

.;D

Sift4G

Uncertain

0.033

D;D

Polyphen

0.92

P;P

Vest4

0.062

MutPred

0.12

Gain of catalytic residue at D164 (P = 0.1044);Gain of catalytic residue at D164 (P = 0.1044);

MVP

0.65

ClinPred

0.15

GERP RS

3.6

Varity_R

0.094

gMVP

0.35

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