rs199623358

chr19-49830085-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_030973.4(MED25):c.689-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,606,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: MED25 NM_030973.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002217
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.168

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-49830085-C-T is Benign according to our data. Variant chr19-49830085-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.689-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000312865.10
MED25	NM_001378355.1	c.689-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.689-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030973.4
MED25	ENST00000538643.5	c.181-426C>T		intron_variant		1
MED25	ENST00000595185.5	c.688+137C>T		intron_variant		1
MED25	ENST00000593767.3	c.689-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3		P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000617 AC: 150 AN: 243000 Hom.: 0 AF XY: 0.000642 AC XY: 85 AN XY: 132420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00378

Gnomad NFE exome AF: 0.000690

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000503 AC: 731 AN: 1453890 Hom.: 0 Cov.: 33 AF XY: 0.000479 AC XY: 346 AN XY: 722830

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00357

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	8.3
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.090		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: rs199623358; hg19: chr19-50333342; COSMIC: COSV57208215; COSMIC: COSV57208215;