19-49834979-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030973.4(MED25):c.1483-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,766 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 27 hom., cov: 32)

Exomes 𝑓: 0.020 ( 338 hom. )

Consequence

MED25
NM_030973.4 splice_region, intron

Scores

Splicing: ADA: 0.00002613

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.121

Publications

5 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: G2P, Ambry Genetics, Orphanet, 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: ClinGen, Orphanet

MED25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-49834979-C-T is Benign according to our data. Variant chr19-49834979-C-T is described in ClinVar as Benign. ClinVar VariationId is 221177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2375/152198) while in subpopulation NFE AF = 0.0227 (1543/67994). AF 95% confidence interval is 0.0218. There are 27 homozygotes in GnomAd4. There are 1129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	NM_030973.4	MANE Select	c.1483-7C>T		splice_region intron	N/A	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.1483-7C>T		splice_region intron	N/A	NP_001365284.1	M0QZQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MED25	ENST00000312865.10	TSL:1 MANE Select	c.1483-7C>T	splice_region intron	N/A	ENSP00000326767.5	Q71SY5-1
MED25	ENST00000538643.5	TSL:1	c.844-7C>T	splice_region intron	N/A	ENSP00000437496.1	Q71SY5-6
MED25	ENST00000595185.5	TSL:1	c.689-1912C>T	intron	N/A	ENSP00000470027.1	M0QYR4

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2374

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00553

Gnomad AMI

AF:

0.00551

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0173

AC:

4345

AN:

251228

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00529

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0468

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0197

AC:

28814

AN:

1461568

Hom.:

338

Cov.:

AF XY:

0.0199

AC XY:

14475

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00409

AC:

137

AN:

33468

American (AMR)

AF:

0.0124

AC:

554

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0474

AC:

1239

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0110

AC:

951

AN:

86242

European-Finnish (FIN)

AF:

0.0128

AC:

682

AN:

53346

Middle Eastern (MID)

AF:

0.0317

AC:

181

AN:

5718

European-Non Finnish (NFE)

AF:

0.0215

AC:

23933

AN:

1111884

Other (OTH)

AF:

0.0188

AC:

1136

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1576

3152

4728

6304

7880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.0156

AC:

2375

AN:

152198

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1129

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00552

AC:

229

AN:

41516

American (AMR)

AF:

0.0136

AC:

208

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

190

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00768

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0117

AC:

124

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0227

AC:

1543

AN:

67994

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

243

365

486

608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0214

Hom.:

Bravo

AF:

0.0151

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0258

EpiControl

AF:

0.0252

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 2 (1)

Charcot-Marie-Tooth disease type 2B2 (1)

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.4

(source)

DANN

Benign

0.64

PhyloP100

-0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0

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

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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

Computational scores

Splicing

Publications

Other links and lift over