19-49835196-C-T

Variant names:

• chr19-49835196-C-T
• rs752522
• NM_030973.4:c.1674+19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030973.4(MED25):​c.1674+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,184 control chromosomes in the GnomAD database, including 16,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1061 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14997 hom.)
• Consequence: MED25 NM_030973.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.688
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-49835196-C-T is Benign according to our data. Variant chr19-49835196-C-T is described in ClinVar as Benign. ClinVar VariationId is 138199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	NM_030973.4	MANE Select	c.1674+19C>T		intron	N/A	NP_112235.2
	MED25	NM_001378355.1		c.1674+19C>T		intron	N/A	NP_001365284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	ENST00000312865.10	TSL:1 MANE Select	c.1674+19C>T		intron	N/A	ENSP00000326767.5
	MED25	ENST00000538643.5	TSL:1	c.1035+19C>T		intron	N/A	ENSP00000437496.1
	MED25	ENST00000595185.5	TSL:1	c.689-1695C>T		intron	N/A	ENSP00000470027.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17067 AN: 151988 Hom.: 1061 Cov.: 32

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.117 AC: 29298 AN: 251098 AF XY: 0.118

Gnomad AFR exome AF: 0.0683

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.139 AC: 203535 AN: 1461078 Hom.: 14997 Cov.: 31 AF XY: 0.138 AC XY: 100238 AN XY: 726886

African (AFR) AF: 0.0673 AC: 2253 AN: 33476

American (AMR) AF: 0.0783 AC: 3500 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3426 AN: 26134

East Asian (EAS) AF: 0.145 AC: 5745 AN: 39694

South Asian (SAS) AF: 0.0762 AC: 6572 AN: 86252

European-Finnish (FIN) AF: 0.103 AC: 5451 AN: 53080

Middle Eastern (MID) AF: 0.136 AC: 786 AN: 5768

European-Non Finnish (NFE) AF: 0.151 AC: 167845 AN: 1111568

Other (OTH) AF: 0.132 AC: 7957 AN: 60384

GnomAD4 genome AF: 0.112 AC: 17065 AN: 152106 Hom.: 1061 Cov.: 32 AF XY: 0.110 AC XY: 8193 AN XY: 74360

African (AFR) AF: 0.0675 AC: 2798 AN: 41480

American (AMR) AF: 0.102 AC: 1555 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3468

East Asian (EAS) AF: 0.144 AC: 743 AN: 5156

South Asian (SAS) AF: 0.0748 AC: 361 AN: 4824

European-Finnish (FIN) AF: 0.104 AC: 1105 AN: 10610

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9681 AN: 67964

Other (OTH) AF: 0.124 AC: 261 AN: 2104

Alfa AF: 0.129 Hom.: 1947

Bravo AF: 0.113

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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: rs752522; hg19: chr19-50338453; COSMIC: COSV57204693; COSMIC: COSV57204693;