rs79635160

Variant names:

• chr19-49835527-C-T
• rs79635160
• NM_030973.4:c.1675-7C>T

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.1675-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,550,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (11 hom.)
• Consequence: MED25 NM_030973.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002592
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.26
• 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: 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=-0.84).
• BP6: Variant 19-49835527-C-T is Benign according to our data. Variant chr19-49835527-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0016 (243/152344) while in subpopulation EAS AF = 0.0255 (132/5184). AF 95% confidence interval is 0.0219. There are 4 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	NM_030973.4	MANE Select	c.1675-7C>T		splice_region intron	N/A	NP_112235.2
	MED25	NM_001378355.1		c.1675-7C>T		splice_region 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.1675-7C>T		splice_region intron	N/A	ENSP00000326767.5
	MED25	ENST00000538643.5	TSL:1	c.1036-7C>T		splice_region intron	N/A	ENSP00000437496.1
	MED25	ENST00000595185.5	TSL:1	c.689-1364C>T		intron	N/A	ENSP00000470027.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152226 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00308 AC: 500 AN: 162230 AF XY: 0.00310

Gnomad AFR exome AF: 0.000110

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.000128

Gnomad EAS exome AF: 0.0280

Gnomad FIN exome AF: 0.000447

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00142 AC: 1988 AN: 1397882 Hom.: 11 Cov.: 33 AF XY: 0.00147 AC XY: 1017 AN XY: 689758

African (AFR) AF: 0.000189 AC: 6 AN: 31728

American (AMR) AF: 0.00137 AC: 50 AN: 36468

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 AN: 24540

East Asian (EAS) AF: 0.0231 AC: 839 AN: 36392

South Asian (SAS) AF: 0.000786 AC: 62 AN: 78856

European-Finnish (FIN) AF: 0.000474 AC: 23 AN: 48494

Middle Eastern (MID) AF: 0.000949 AC: 4 AN: 4214

European-Non Finnish (NFE) AF: 0.000822 AC: 887 AN: 1079510

Other (OTH) AF: 0.00201 AC: 116 AN: 57680

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152344 Hom.: 4 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74492

African (AFR) AF: 0.000313 AC: 13 AN: 41590

American (AMR) AF: 0.00176 AC: 27 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68016

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000890 Hom.: 0

Bravo AF: 0.00184

Asia WGS AF: 0.0120 AC: 41 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 type 2 (1)
-	-	1	Charcot-Marie-Tooth disease type 2B2;C4225323:Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (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	-0.84
CADD	Benign	1.6
DANN	Benign	0.54
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0040
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: rs79635160; hg19: chr19-50338784;