9-133341510-C-T

Variant names:

• chr9-133341510-C-T
• rs377187824
• NM_133640.5:c.598G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_133640.5(MED22):​c.598G>A​(p.Ala200Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,510,652 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: MED22 NM_133640.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015460998).
• BP6: Variant 9-133341510-C-T is Benign according to our data. Variant chr9-133341510-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3394636.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED22	NM_133640.5	c.598G>A	p.Ala200Thr	missense_variant	Exon 5 of 5	ENST00000343730.10	NP_598395.1
MED22	NM_181491.3	c.*2605G>A		3_prime_UTR_variant	Exon 4 of 4		NP_852468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED22	ENST00000343730.10	c.598G>A	p.Ala200Thr	missense_variant	Exon 5 of 5	1	NM_133640.5	ENSP00000342343.5
MED22	ENST00000610888	c.*2605G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000478773.1
MED22	ENST00000614493	c.*2605G>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000481493.1
MED22	ENST00000610672.4	c.598G>A	p.Ala200Thr	missense_variant	Exon 5 of 5	2		ENSP00000482438.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152208 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: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000541 AC: 9 AN: 166434 Hom.: 0 AF XY: 0.0000539 AC XY: 5 AN XY: 92736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000531

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000832

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000589 AC: 80 AN: 1358444 Hom.: 0 Cov.: 29 AF XY: 0.0000611 AC XY: 41 AN XY: 671316

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: 0.0000289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000690

Gnomad4 OTH exome AF: 0.0000717

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 05, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.18	.;N
REVEL	Benign	0.059
Sift	Benign	0.55	.;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.0	B;B
Vest4		0.030
MVP		0.15
ClinPred		0.12	T
GERP RS		-0.22
Varity_R		0.016
gMVP		0.20

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

Other links and lift over

dbSNP: rs377187824; hg19: chr9-136208360;