chr19-49830201-G-C

Variant names:

• chr19-49830201-G-C
• rs1015978148
• NM_030973.4:c.802G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030973.4(MED25):​c.802G>C​(p.Val268Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V268I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 0 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: Ambry Genetics, Orphanet, G2P, 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: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32934558).

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.802G>C	p.Val268Leu	missense	Exon 7 of 18	NP_112235.2
	MED25	NM_001378355.1		c.802G>C	p.Val268Leu	missense	Exon 7 of 18	NP_001365284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	ENST00000312865.10	TSL:1 MANE Select	c.802G>C	p.Val268Leu	missense	Exon 7 of 18	ENSP00000326767.5
	MED25	ENST00000538643.5	TSL:1	c.181-310G>C		intron	N/A	ENSP00000437496.1
	MED25	ENST00000595185.5	TSL:1	c.688+253G>C		intron	N/A	ENSP00000470027.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.27
Sift	Benign	0.033	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.11		Gain of catalytic residue at V268 (P = 0.0774)
MVP		0.77
MPC		1.1
ClinPred		0.71	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.26
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1015978148; hg19: chr19-50333458;