19-49836348-G-A

Variant names:

• chr19-49836348-G-A
• rs371157406
• NM_030973.4:c.2088G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_030973.4(MED25):​c.2088G>A​(p.Leu696Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,609,380 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 0.690
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.033).
• BP6: Variant 19-49836348-G-A is Benign according to our data. Variant chr19-49836348-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152298) while in subpopulation NFE AF = 0.00351 (239/68006). AF 95% confidence interval is 0.00315. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.2088G>A	p.Leu696Leu	synonymous	Exon 17 of 18	NP_112235.2	Q71SY5-1
	MED25	NM_001378355.1		c.2088G>A	p.Leu696Leu	synonymous	Exon 17 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.2088G>A	p.Leu696Leu	synonymous	Exon 17 of 18	ENSP00000326767.5	Q71SY5-1
	MED25	ENST00000538643.5	TSL:1	c.1449G>A	p.Leu483Leu	synonymous	Exon 12 of 13	ENSP00000437496.1	Q71SY5-6
	MED25	ENST00000595185.5	TSL:1	c.689-543G>A		intron	N/A	ENSP00000470027.1	M0QYR4

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00268 AC: 632 AN: 235818 AF XY: 0.00251

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00408

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00304 AC: 4424 AN: 1457082 Hom.: 8 Cov.: 32 AF XY: 0.00297 AC XY: 2149 AN XY: 724582

African (AFR) AF: 0.000389 AC: 13 AN: 33404

American (AMR) AF: 0.00246 AC: 109 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.00323 AC: 84 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.000759 AC: 65 AN: 85664

European-Finnish (FIN) AF: 0.00449 AC: 233 AN: 51900

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00343 AC: 3803 AN: 1110308

Other (OTH) AF: 0.00185 AC: 111 AN: 60106

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74458

African (AFR) AF: 0.000698 AC: 29 AN: 41574

American (AMR) AF: 0.00294 AC: 45 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00351 AC: 239 AN: 68006

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

Alfa AF: 0.00237 Hom.: 0

Bravo AF: 0.00232

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)
-	-	1	not specified (1)
-	1	-	Polyneuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.45
PhyloP100		0.69
Mutation Taster		=100/0	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: rs371157406; hg19: chr19-50339605; COSMIC: COSV57204599; COSMIC: COSV57204599;