chr19-49818439-A-T

Variant names:

• chr19-49818439-A-T
• rs1055260585
• NM_030973.4:c.98A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030973.4(MED25):​c.98A>T​(p.Glu33Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.98A>T	p.Glu33Val	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.98A>T	p.Glu33Val	missense_variant	Exon 1 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.98A>T	p.Glu33Val	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T;T;D;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.9	.;.;.;.;L;.;L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	.;.;.;.;D;.;D;.;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	.;.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.036	D;D;T;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.;.
Vest4		0.79
MutPred		0.34		Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);Loss of ubiquitination at K37 (P = 0.045);
MVP		0.75
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1055260585; hg19: chr19-50321696;