NM_030973.4:c.-12A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030973.4(MED25):c.-12A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,571,294 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0092 ( 90 hom. )

Consequence

MED25
NM_030973.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.118

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-49818330-A-G is Benign according to our data. Variant chr19-49818330-A-G is described in ClinVar as [Benign]. Clinvar id is 138201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49818330-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2198/152258) while in subpopulation AFR AF= 0.0287 (1191/41568). AF 95% confidence interval is 0.0273. There are 24 homozygotes in gnomad4. There are 983 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4 link	c.-12A>G		5_prime_UTR_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2	Q71SY5-1
MED25	NM_001378355.1 link	c.-12A>G		5_prime_UTR_variant	Exon 1 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865 link	c.-12A>G		5_prime_UTR_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5		Q71SY5-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2192

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00968

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.00714

AC:

1274

AN:

178518

Hom.:

AF XY:

0.00658

AC XY:

643

AN XY:

97676

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.00703

Gnomad ASJ exome

AF:

0.00981

Gnomad EAS exome

AF:

0.000911

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00211

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00924

AC:

13117

AN:

1419036

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

6283

AN XY:

702652

show subpopulations

Gnomad4 AFR exome

AF:

0.0297

Gnomad4 AMR exome

AF:

0.00726

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.000404

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.00218

Gnomad4 NFE exome

AF:

0.00976

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.0144

AC:

2198

AN:

152258

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

983

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0287

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00968

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0158

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome

Benign:1

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.9

DANN

Benign

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over