19-49818343-T-G

Position:

• chr19-49818343-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 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

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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 id is 3063666.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED25	NM_030973.4	c.2T>G	p.Met1?	start_lost	1/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.2T>G	p.Met1?	start_lost	1/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.2T>G	p.Met1?	start_lost	1/18	1	NM_030973.4	ENSP00000326767

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 24, 2024

Variant summary: MED25 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. A rare, homozygous missense variant p.Tyr39Cys, upstream of the next downstream in-frame Met104, has been reported in at-least 4 families with Basel-Vanagait-Smirin-Yosef syndrome, and segregated with disease; subsequent functional study found p.Tyr39Cys impaired MED25 interaction with the Mediator complex in mammalian cells (PMID: 25792360, ClinVar ID 203445). The current variant was absent in 203948 control chromosomes. To our knowledge, no occurrence of c.2T>G in individuals affected with Congenital Cataract-Microcephaly Flammeus Simplex-Severe Intellectual Disability Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.4	.;.;.;.;N;.;N;.;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.040	D;D;D;D;D;D;D;D;D
Polyphen		0.93	.;.;.;.;P;.;.;.;.
Vest4		0.92
MutPred		0.99		Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);
MVP		0.74
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.67

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50321600;