chr19-49818601-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_030973.4(MED25):c.165G>A(p.Thr55Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,614,030 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 83 hom., cov: 33)

Exomes 𝑓: 0.029 ( 1248 hom. )

Consequence

MED25
NM_030973.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.285

Publications

6 publications found

Variant links:

Genes affected

MED25 (HGNC:28845): (mediator complex subunit 25) This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]

MED25 Gene-Disease associations (from GenCC):

congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

MED25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 19-49818601-G-A is Benign according to our data. Variant chr19-49818601-G-A is described in ClinVar as Benign. ClinVar VariationId is 195384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.285 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030973.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	NM_030973.4	MANE Select	c.165G>A	p.Thr55Thr	synonymous	Exon 2 of 18	NP_112235.2
	MED25	NM_001378355.1		c.165G>A	p.Thr55Thr	synonymous	Exon 2 of 18	NP_001365284.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MED25	ENST00000312865.10	TSL:1 MANE Select	c.165G>A	p.Thr55Thr	synonymous	Exon 2 of 18	ENSP00000326767.5
MED25	ENST00000538643.5	TSL:1	c.165G>A	p.Thr55Thr	synonymous	Exon 2 of 13	ENSP00000437496.1
MED25	ENST00000595185.5	TSL:1	c.165G>A	p.Thr55Thr	synonymous	Exon 2 of 7	ENSP00000470027.1

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3397

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0375

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.125

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0355

AC:

8922

AN:

251342

AF XY:

0.0399

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00879

Gnomad ASJ exome

AF:

0.0391

Gnomad EAS exome

AF:

0.0570

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0291

AC:

42509

AN:

1461720

Hom.:

1248

Cov.:

AF XY:

0.0318

AC XY:

23159

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0118

AC:

395

AN:

33480

American (AMR)

AF:

0.00868

AC:

388

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

1031

AN:

26132

East Asian (EAS)

AF:

0.0724

AC:

2873

AN:

39698

South Asian (SAS)

AF:

0.118

AC:

10182

AN:

86254

European-Finnish (FIN)

AF:

0.0217

AC:

1155

AN:

53314

Middle Eastern (MID)

AF:

0.0348

AC:

201

AN:

5768

European-Non Finnish (NFE)

AF:

0.0220

AC:

24459

AN:

1111954

Other (OTH)

AF:

0.0302

AC:

1825

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2564

5129

7693

10258

12822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1034

2068

3102

4136

5170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0224

AC:

3408

AN:

152310

Hom.:

Cov.:

AF XY:

0.0235

AC XY:

1753

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0111

AC:

463

AN:

41572

American (AMR)

AF:

0.0114

AC:

174

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0375

AC:

130

AN:

3470

East Asian (EAS)

AF:

0.0595

AC:

309

AN:

5190

South Asian (SAS)

AF:

0.125

AC:

602

AN:

4824

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1441

AN:

68018

Other (OTH)

AF:

0.0284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0190

Asia WGS

AF:

0.122

AC:

424

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease type 2

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-0.28

PromoterAI

-0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over