rs145770066

Positions:

• chr19-49830790-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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:10 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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.1004C>T	p.Ala335Val	missense_variant	9/18	1	NM_030973.4	ENSP00000326767
MED25	ENST00000538643.5	c.365C>T	p.Ala122Val	missense_variant	4/13	1		ENSP00000437496
MED25	ENST00000595185.5	c.688+842C>T		intron_variant		1		ENSP00000470027
MED25	ENST00000593767.3	c.1004C>T	p.Ala335Val	missense_variant	9/18	3		ENSP00000470692	P1

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

GnomAD3 exomes AF: 0.00384 AC: 952 AN: 247818 Hom.: 3 AF XY: 0.00384 AC XY: 517 AN XY: 134684

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 SAS exome AF: 0.000753

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

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.00427

Gnomad4 NFE exome AF: 0.00836

Gnomad4 OTH exome AF: 0.00644

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

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00725

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00610 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:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MED25: BS2 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

-

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2020

- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

MED25-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2020

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;.;.
MutationTaster	Benign	0.10	A;A
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

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;