19-49835536-G-C

Variant names:

• chr19-49835536-G-C
• rs369006637
• NM_030973.4:c.1677G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_030973.4(MED25):​c.1677G>C​(p.Met559Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,557,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: MED25 NM_030973.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.93
• Publications: 1 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: G2P, Ambry Genetics, Orphanet, 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: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013620943).
• BP6: Variant 19-49835536-G-C is Benign according to our data. Variant chr19-49835536-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476802.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000433 (66/152304) while in subpopulation AFR AF = 0.0014 (58/41566). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030973.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	NM_030973.4	MANE Select	c.1677G>C	p.Met559Ile	missense splice_region	Exon 15 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.1677G>C	p.Met559Ile	missense splice_region	Exon 15 of 18	NP_001365284.1	M0QZQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED25	ENST00000312865.10	TSL:1 MANE Select	c.1677G>C	p.Met559Ile	missense splice_region	Exon 15 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000538643.5	TSL:1	c.1038G>C	p.Met346Ile	missense splice_region	Exon 10 of 13	ENSP00000437496.1	Q71SY5-6
	MED25	ENST00000595185.5	TSL:1	c.689-1355G>C		intron	N/A	ENSP00000470027.1	M0QYR4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000118 AC: 20 AN: 168864 AF XY: 0.0000552

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.0000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000590

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000975 AC: 137 AN: 1405204 Hom.: 0 Cov.: 33 AF XY: 0.0000922 AC XY: 64 AN XY: 694026

African (AFR) AF: 0.00263 AC: 84 AN: 31972

American (AMR) AF: 0.000133 AC: 5 AN: 37528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 36694

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48826

Middle Eastern (MID) AF: 0.000460 AC: 2 AN: 4344

European-Non Finnish (NFE) AF: 0.0000194 AC: 21 AN: 1083334

Other (OTH) AF: 0.000397 AC: 23 AN: 57982

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74462

African (AFR) AF: 0.00140 AC: 58 AN: 41566

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.000593

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000144 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.20
Sift	Uncertain	0.023	D
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.43		Gain of loop (P = 0.0166)
MVP		0.65
MPC		0.20
ClinPred		0.030	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.25
Mutation Taster		=87/13	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: rs369006637; hg19: chr19-50338793;