chr19-49818330-A-G

Variant names:

• chr19-49818330-A-G
• rs114843375
• NM_030973.4:c.-12A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: Benign. The variant received -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 VariationId is 138201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.-12A>G		5_prime_UTR	Exon 1 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.-12A>G		5_prime_UTR	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.-12A>G		5_prime_UTR	Exon 1 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000929730.1		c.-12A>G		5_prime_UTR	Exon 1 of 18	ENSP00000599789.1
	MED25	ENST00000593767.3	TSL:3	c.-12A>G		5_prime_UTR	Exon 1 of 18	ENSP00000470692.3	M0QZQ2

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

GnomAD2 exomes AF: 0.00714 AC: 1274 AN: 178518 AF XY: 0.00658

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 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

African (AFR) AF: 0.0297 AC: 958 AN: 32302

American (AMR) AF: 0.00726 AC: 278 AN: 38312

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 262 AN: 25420

East Asian (EAS) AF: 0.000404 AC: 15 AN: 37112

South Asian (SAS) AF: 0.00153 AC: 128 AN: 83420

European-Finnish (FIN) AF: 0.00218 AC: 107 AN: 49070

Middle Eastern (MID) AF: 0.0133 AC: 67 AN: 5050

European-Non Finnish (NFE) AF: 0.00976 AC: 10641 AN: 1089752

Other (OTH) AF: 0.0113 AC: 661 AN: 58598

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

African (AFR) AF: 0.0287 AC: 1191 AN: 41568

American (AMR) AF: 0.0133 AC: 203 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00968 AC: 658 AN: 67994

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0122 Hom.: 3

Bravo AF: 0.0158

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.33
PhyloP100		0.12
PromoterAI		0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=300/0	polymorphism

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

dbSNP: rs114843375; hg19: chr19-50321587;