Genetic Variant NM_030973.4:c.664C>T (chr19-49829924-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_030973.4(MED25):c.664C>T(p.Leu222Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000793 in 1,612,930 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 2 hom. )

Consequence

MED25
NM_030973.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.51

Publications

0 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024597228).

BP6

Variant 19-49829924-C-T is Benign according to our data. Variant chr19-49829924-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 215945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.51 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000473 (72/152302) while in subpopulation NFE AF = 0.000941 (64/68020). AF 95% confidence interval is 0.000755. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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.664C>T	p.Leu222Leu	synonymous	Exon 6 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.664C>T	p.Leu222Leu	synonymous	Exon 6 of 18	NP_001365284.1	M0QZQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MED25	ENST00000312865.10	TSL:1 MANE Select	c.664C>T	p.Leu222Leu	synonymous	Exon 6 of 18	ENSP00000326767.5	Q71SY5-1
MED25	ENST00000595185.5	TSL:1	c.664C>T	p.Leu222Leu	synonymous	Exon 6 of 7	ENSP00000470027.1	M0QYR4
MED25	ENST00000538643.5	TSL:1	c.181-587C>T		intron	N/A	ENSP00000437496.1	Q71SY5-6

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000596

AC:

149

AN:

250116

AF XY:

0.000657

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000826

AC:

1207

AN:

1460628

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

576

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000728

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

52742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00101

AC:

1121

AN:

1111542

Other (OTH)

AF:

0.000828

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000473

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000717

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 2 (1)

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.74

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.38

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.77

PhyloP100

2.5

Sift4G

Benign

0.26

Vest4

0.38

MVP

0.63

ClinPred

0.046

GERP RS

5.4

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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