chr19-49818356-C-G

Variant names:

• chr19-49818356-C-G
• rs1568617655
• NM_030973.4:c.15C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_030973.4(MED25):​c.15C>G​(p.Ser5Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S5S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 0 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: 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 (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.15C>G	p.Ser5Ser	synonymous_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.15C>G	p.Ser5Ser	synonymous_variant	Exon 1 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.15C>G	p.Ser5Ser	synonymous_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447652 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719422

African (AFR) AF: 0.0000302 AC: 1 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 42290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 85282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105146

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-1.4
PromoterAI		0.046	Neutral

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: rs1568617655; hg19: chr19-50321613;