chr19-49818343-T-G

Variant names:

• chr19-49818343-T-G
• NM_030973.4:c.2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_030973.4(MED25):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MED25 NM_030973.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.06
• 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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 104 codons. Genomic position: 49828453. Lost 0.138 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-49818343-T-G is Pathogenic according to our data. Variant chr19-49818343-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3063666.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2T>G	p.Met1?	start_lost	Exon 1 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.2T>G	p.Met1?	start_lost	Exon 1 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.2T>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000538643.5	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000437496.1	Q71SY5-6
	MED25	ENST00000595185.5	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000470027.1	M0QYR4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.097	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.28	D
PhyloP100		4.1
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.040	D
Polyphen		0.93	P
Vest4		0.92
MutPred		0.99		Gain of methylation at M1 (P = 0.0173)
MVP		0.74
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		0.011	Neutral
Varity_R		0.98
gMVP		0.67
Mutation Taster		=19/181	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chr19-50321600;