chr9-133341657-C-T

Variant names:

• chr9-133341657-C-T
• rs373755320
• NM_133640.5:c.451G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133640.5(MED22):​c.451G>A​(p.Glu151Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000672 in 1,608,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: MED22 NM_133640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3142138).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED22	NM_133640.5	MANE Select	c.451G>A	p.Glu151Lys	missense	Exon 5 of 5	NP_598395.1	Q15528-1
	MED22	NM_181491.3		c.*2458G>A		3_prime_UTR	Exon 4 of 4	NP_852468.1	Q15528-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED22	ENST00000343730.10	TSL:1 MANE Select	c.451G>A	p.Glu151Lys	missense	Exon 5 of 5	ENSP00000342343.5	Q15528-1
	MED22	ENST00000610888.4	TSL:1	c.*2458G>A		3_prime_UTR	Exon 4 of 4	ENSP00000478773.1	Q15528-2
	MED22	ENST00000614493.4	TSL:2	c.*2458G>A		3_prime_UTR	Exon 4 of 4	ENSP00000481493.1	Q15528-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000412 AC: 10 AN: 242882 AF XY: 0.0000379

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000915

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 101 AN: 1455848 Hom.: 0 Cov.: 29 AF XY: 0.0000539 AC XY: 39 AN XY: 724162

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39018

South Asian (SAS) AF: 0.00 AC: 0 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.0000829 AC: 92 AN: 1109374

Other (OTH) AF: 0.0000997 AC: 6 AN: 60170

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74490

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.037
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.70
MVP		0.50
ClinPred		0.24	T
GERP RS		4.6
Varity_R		0.44
gMVP		0.73
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373755320; hg19: chr9-136208507; COSMIC: COSV59297284; COSMIC: COSV59297284;