rs781140315

Variant names:

• chr19-49828983-C-G
• rs781140315
• NM_030973.4:c.418C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-49828983-C-G
• chr19-49828983-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_030973.4(MED25):​c.418C>G​(p.Arg140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. R140Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 5 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-49828983-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16228676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 18	1	NM_030973.4	ENSP00000326767.5
MED25	ENST00000595185.5	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 7	1		ENSP00000470027.1
MED25	ENST00000538643.5	c.181-1528C>G		intron_variant	Intron 2 of 12	1		ENSP00000437496.1
MED25	ENST00000593767.3	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 18	3		ENSP00000470692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251360 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.15	.;T;D;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;L;.;.
PhyloP100		1.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	.;.;D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0030	.;.;D;.;.
Sift4G	Benign	0.32	T;D;T;T;T
Polyphen		0.0020	.;.;B;.;.
Vest4		0.70
MutPred		0.58		Gain of catalytic residue at V141 (P = 0.0244);Gain of catalytic residue at V141 (P = 0.0244);Gain of catalytic residue at V141 (P = 0.0244);Gain of catalytic residue at V141 (P = 0.0244);Gain of catalytic residue at V141 (P = 0.0244);
MVP		0.18
MPC		0.49
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.45
gMVP		0.86
Mutation Taster		=47/53	disease causing

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: rs781140315; hg19: chr19-50332240;