rs545524810

Variant names:

• chr19-49818370-G-A
• rs545524810
• NM_030973.4:c.29G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49818370-G-A
• chr19-49818370-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030973.4(MED25):​c.29G>A​(p.Arg10His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,278 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.98
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28477365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.29G>A	p.Arg10His	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.29G>A	p.Arg10His	missense_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.29G>A	p.Arg10His	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456278 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724086

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 43808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 85884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52508

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109408

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0026	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.061	.;.;T;T;T;.;.;.;.
Eigen	Benign	0.060
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.075	N
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;N;.;.
PhyloP100		4.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.53	.;.;.;.;N;.;N;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0060	.;.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D
Polyphen		0.77	.;.;.;.;P;.;.;.;.
Vest4		0.47
MutPred		0.30		Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);
MVP		0.71
MPC		0.82
ClinPred		0.91	D
GERP RS		4.7
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.13
gMVP		0.17
Mutation Taster		=96/4	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: rs545524810; hg19: chr19-50321627;