rs145770066

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/22 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
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015774012).
• BP6: Variant 19-49830790-C-T is Benign according to our data. Variant chr19-49830790-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1324.
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1004C>T	p.Ala335Val	missense	Exon 9 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.1004C>T	p.Ala335Val	missense	Exon 9 of 18	NP_001365284.1	M0QZQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	ENST00000312865.10	TSL:1 MANE Select	c.1004C>T	p.Ala335Val	missense	Exon 9 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000538643.5	TSL:1	c.365C>T	p.Ala122Val	missense	Exon 4 of 13	ENSP00000437496.1	Q71SY5-6
	MED25	ENST00000595185.5	TSL:1	c.688+842C>T		intron	N/A	ENSP00000470027.1	M0QYR4

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

African (AFR) AF: 0.000867 AC: 29 AN: 33462

American (AMR) AF: 0.00114 AC: 51 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000673 AC: 58 AN: 86238

European-Finnish (FIN) AF: 0.00427 AC: 226 AN: 52974

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00836 AC: 9297 AN: 1111450

Other (OTH) 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

African (AFR) AF: 0.00156 AC: 65 AN: 41556

American (AMR) AF: 0.00333 AC: 51 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4804

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (2)
-	1	1	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	1	-	Charcot-Marie-Tooth disease type 2B2 (2)
-	-	1	MED25-related disorder (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.29
Sift	Benign	0.17	T
Sift4G	Benign	0.25	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

Other links and lift over

dbSNP: rs145770066; hg19: chr19-50334047; COSMIC: COSV106096525; COSMIC: COSV106096525;