rs145770066

Variant names:

• chr19-49830790-C-T
• rs145770066
• NM_030973.4:c.1004C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030973.4(MED25):​c.1004C>T​(p.Ala335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,613,014 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A335T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (41 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:11 O:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015774012).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00428 (651/152228) while in subpopulation NFE AF = 0.00725 (493/67998). AF 95% confidence interval is 0.00672. There are 3 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.1004C>T	p.Ala335Val	missense_variant	Exon 9 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.1004C>T	p.Ala335Val	missense_variant	Exon 9 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.1004C>T	p.Ala335Val	missense_variant	Exon 9 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 650 AN: 152110 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00384 AC: 952 AN: 247818 AF XY: 0.00384

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00690 AC: 10082 AN: 1460786 Hom.: 41 Cov.: 33 AF XY: 0.00672 AC XY: 4886 AN XY: 726696

Gnomad4 AFR exome AF: 0.000867 AC: 29 AN: 33462

Gnomad4 AMR exome AF: 0.00114 AC: 51 AN: 44718

Gnomad4 ASJ exome AF: 0.00119 AC: 31 AN: 26118

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.000673 AC: 58 AN: 86238

Gnomad4 FIN exome AF: 0.00427 AC: 226 AN: 52974

Gnomad4 NFE exome AF: 0.00836 AC: 9297 AN: 1111450

Gnomad4 Remaining exome AF: 0.00644 AC: 389 AN: 60362

GnomAD4 genome AF: 0.00428 AC: 651 AN: 152228 Hom.: 3 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74424

Gnomad4 AFR AF: 0.00156 AC: 0.00156415 AN: 0.00156415

Gnomad4 AMR AF: 0.00333 AC: 0.00333377 AN: 0.00333377

Gnomad4 ASJ AF: 0.00115 AC: 0.00115207 AN: 0.00115207

Gnomad4 EAS AF: 0.000194 AC: 0.000193648 AN: 0.000193648

Gnomad4 SAS AF: 0.000833 AC: 0.000832639 AN: 0.000832639

Gnomad4 FIN AF: 0.00264 AC: 0.00263653 AN: 0.00263653

Gnomad4 NFE AF: 0.00725 AC: 0.00725021 AN: 0.00725021

Gnomad4 OTH AF: 0.00237 AC: 0.00236967 AN: 0.00236967

Alfa AF: 0.00597 Hom.: 6

Bravo AF: 0.00413

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00364 AC: 442

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MED25: BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MED25 c.1004C>T (p.Ala335Val) results in a non-conservative amino acid change located in the Mediator complex subunit 25 synapsin 1 (IPR021397) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0067 in 1613014 control chromosomes in the gnomAD database (v4), including 44 homozygotes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MED25 causing Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome phenotype (0.0011). To our knowledge, no occurrence of c.1004C>T in individuals affected with Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1324). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 14, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2B2 Uncertain:1 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2009

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Benign:2

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait Pathogenic:1

-

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MED25-related disorder Benign:1

Jul 15, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	.;T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.74	T;T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	.;N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.010	.;N;N;.
REVEL	Benign	0.29
Sift	Benign	0.17	.;T;T;.
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.021	.;B;.;.
Vest4		0.48
MVP		0.64
MPC		0.52
ClinPred		0.0077	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.22
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145770066; hg19: chr19-50334047; COSMIC: COSV106096525; COSMIC: COSV106096525;