19-49818330-A-G

Position:

• chr19-49818330-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030973.4(MED25):​c.-12A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,571,294 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (90 hom.)
• Consequence: MED25 NM_030973.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.118

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-49818330-A-G is Benign according to our data. Variant chr19-49818330-A-G is described in ClinVar as [Benign]. Clinvar id is 138201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49818330-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2198/152258) while in subpopulation AFR AF= 0.0287 (1191/41568). AF 95% confidence interval is 0.0273. There are 24 homozygotes in gnomad4. There are 983 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED25	NM_030973.4	c.-12A>G		5_prime_UTR_variant	1/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.-12A>G		5_prime_UTR_variant	1/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.-12A>G		5_prime_UTR_variant	1/18	1	NM_030973.4	ENSP00000326767

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152140 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00968

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00714 AC: 1274 AN: 178518 Hom.: 11 AF XY: 0.00658 AC XY: 643 AN XY: 97676

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.00981

Gnomad EAS exome AF: 0.000911

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00211

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00924 AC: 13117 AN: 1419036 Hom.: 90 Cov.: 34 AF XY: 0.00894 AC XY: 6283 AN XY: 702652

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.00726

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00976

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0144 AC: 2198 AN: 152258 Hom.: 24 Cov.: 33 AF XY: 0.0132 AC XY: 983 AN XY: 74456

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00968

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0116 Hom.: 3

Bravo AF: 0.0158

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 20, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

LitVar

Other links and lift over

dbSNP: rs114843375; hg19: chr19-50321587;