rs185100172

Variant names:

• chr19-49835774-C-T
• rs185100172
• NM_030973.4:c.1794C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378355.1(MED25):​c.1794C>T​(p.Ala598Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 1,608,894 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (86 hom.)
• Consequence: MED25 NM_001378355.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.705
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-49835774-C-T is Benign according to our data. Variant chr19-49835774-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.705 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00504 (768/152284) while in subpopulation SAS AF = 0.019 (92/4832). AF 95% confidence interval is 0.0159. There are 3 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378355.1. 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.1794C>T	p.Ala598Ala	synonymous	Exon 16 of 18	NP_112235.2
	MED25	NM_001378355.1		c.1794C>T	p.Ala598Ala	synonymous	Exon 16 of 18	NP_001365284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	ENST00000312865.10	TSL:1 MANE Select	c.1794C>T	p.Ala598Ala	synonymous	Exon 16 of 18	ENSP00000326767.5
	MED25	ENST00000538643.5	TSL:1	c.1155C>T	p.Ala385Ala	synonymous	Exon 11 of 13	ENSP00000437496.1
	MED25	ENST00000595185.5	TSL:1	c.689-1117C>T		intron	N/A	ENSP00000470027.1

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 767 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00716 AC: 1709 AN: 238760 AF XY: 0.00839

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00345

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.000388

Gnomad FIN exome AF: 0.00549

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00783 AC: 11405 AN: 1456610 Hom.: 86 Cov.: 32 AF XY: 0.00827 AC XY: 5991 AN XY: 724664

African (AFR) AF: 0.00144 AC: 48 AN: 33398

American (AMR) AF: 0.00367 AC: 164 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00330 AC: 86 AN: 26072

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39606

South Asian (SAS) AF: 0.0217 AC: 1867 AN: 86010

European-Finnish (FIN) AF: 0.00522 AC: 271 AN: 51918

Middle Eastern (MID) AF: 0.00695 AC: 40 AN: 5756

European-Non Finnish (NFE) AF: 0.00764 AC: 8478 AN: 1109062

Other (OTH) AF: 0.00742 AC: 446 AN: 60146

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152284 Hom.: 3 Cov.: 33 AF XY: 0.00526 AC XY: 392 AN XY: 74464

African (AFR) AF: 0.00140 AC: 58 AN: 41566

American (AMR) AF: 0.00359 AC: 55 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4832

European-Finnish (FIN) AF: 0.00423 AC: 45 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00710 AC: 483 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00570 Hom.: 1

Bravo AF: 0.00470

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	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	-0.66
CADD	Benign	6.6
DANN	Benign	0.46
PhyloP100		-0.70
Mutation Taster		=100/0	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: rs185100172; hg19: chr19-50339031;