rs193291405

Variant names:

• chr19-49835586-C-G
• rs193291405
• NM_030973.4:c.1727C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-49835586-C-G
• chr19-49835586-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030973.4(MED25):​c.1727C>G​(p.Ala576Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,565,174 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A576V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (8 hom., cov: 32)
  • Exomes 𝑓: 0.015 (286 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.65
• Publications: 4 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054638684).
• BP6: Variant 19-49835586-C-G is Benign according to our data. Variant chr19-49835586-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00812 (1237/152330) while in subpopulation NFE AF = 0.0142 (966/68022). AF 95% confidence interval is 0.0135. There are 8 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.1727C>G	p.Ala576Gly	missense	Exon 15 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.1727C>G	p.Ala576Gly	missense	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.1727C>G	p.Ala576Gly	missense	Exon 15 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000538643.5	TSL:1	c.1088C>G	p.Ala363Gly	missense	Exon 10 of 13	ENSP00000437496.1	Q71SY5-6
	MED25	ENST00000595185.5	TSL:1	c.689-1305C>G		intron	N/A	ENSP00000470027.1	M0QYR4

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1238 AN: 152212 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00656 AC: 1130 AN: 172182 AF XY: 0.00666

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00794

GnomAD4 exome AF: 0.0151 AC: 21321 AN: 1412844 Hom.: 286 Cov.: 33 AF XY: 0.0145 AC XY: 10132 AN XY: 698354

African (AFR) AF: 0.00260 AC: 84 AN: 32270

American (AMR) AF: 0.00342 AC: 131 AN: 38264

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 36980

South Asian (SAS) AF: 0.000286 AC: 23 AN: 80360

European-Finnish (FIN) AF: 0.00526 AC: 258 AN: 49062

Middle Eastern (MID) AF: 0.000404 AC: 2 AN: 4954

European-Non Finnish (NFE) AF: 0.0183 AC: 19899 AN: 1087284

Other (OTH) AF: 0.0158 AC: 920 AN: 58364

GnomAD4 genome AF: 0.00812 AC: 1237 AN: 152330 Hom.: 8 Cov.: 32 AF XY: 0.00698 AC XY: 520 AN XY: 74486

African (AFR) AF: 0.00281 AC: 117 AN: 41584

American (AMR) AF: 0.00497 AC: 76 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 966 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00673 Hom.: 4

Bravo AF: 0.00876

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00323 AC: 14

ESP6500EA AF: 0.0112 AC: 95

ExAC AF: 0.00440 AC: 518

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.18
Sift	Uncertain	0.029	D
Sift4G	Benign	0.80	T
Polyphen		0.034	B
Vest4		0.26
MVP		0.47
MPC		0.13
ClinPred		0.0032	T
GERP RS		4.7
Varity_R		0.061
gMVP		0.30
Mutation Taster		=95/5	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: rs193291405; hg19: chr19-50338843; COSMIC: COSV99075182; COSMIC: COSV99075182;