Genetic Variant PTOV1-AS1:n.2144C>T (chr19-49838650-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_001378355.1(MED25):c.2217G>A(p.Val739Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 457,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

MED25
NM_001378355.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.22

Publications

0 publications found

Variant links:

Genes affected

PTOV1-AS1 (HGNC:44174): (PTOV1 antisense RNA 1)

PTOV1-AS1 links:

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

MED25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.019).

BP6

Variant 19-49838650-G-A is Benign according to our data. Variant chr19-49838650-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3771016.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_001378355.1 link	c.2217G>A	p.Val739Val	synonymous_variant	Exon 18 of 18		NP_001365284.1
PTOV1-AS1	NR_040037.1 link	n.2144C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTOV1-AS1	ENST00000596521.1 link	n.2144C>T		non_coding_transcript_exon_variant	Exon 4 of 4	1
MED25	ENST00000593767.3 link	c.2217G>A	p.Val739Val	synonymous_variant	Exon 18 of 18	3		ENSP00000470692.3		M0QZQ2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000361

AC:

AN:

138316

AF XY:

0.0000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000590

AC:

AN:

304942

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

173594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8628

American (AMR)

AF:

0.0000367

AC:

AN:

27282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10790

East Asian (EAS)

AF:

0.00

AC:

AN:

9210

South Asian (SAS)

AF:

0.000100

AC:

AN:

59744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13270

Middle Eastern (MID)

AF:

0.000359

AC:

AN:

2784

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

158974

Other (OTH)

AF:

0.0000701

AC:

AN:

14260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MED25: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-49838650-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over