rs145770066

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). 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: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 GnomAd at 3 AR gene

Transcripts

RefSeq

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

Ensembl

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

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

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

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

-

- -

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

Invitae

Jan 29, 2024

- -

MED25-related disorder Benign:1

Likely benign, criteria provided, single submitter

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
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
MutationTaster	Benign	0.10	A;A
PrimateAI	Uncertain	0.70	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;