17-40022407-C-A

Variant names:

• chr17-40022407-C-A
• rs137866788
• NM_014815.4:c.2510G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014815.4(MED24):​c.2510G>T​(p.Arg837Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,470 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R837H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED24 NM_014815.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 2 publications found

Genes affected

MED24 (HGNC:22963): (mediator complex subunit 24) This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, possibly by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014815.4. 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
	MED24	NM_014815.4	MANE Select	c.2510G>T	p.Arg837Leu	missense	Exon 22 of 26	NP_055630.2
	MED24	NM_001330211.2		c.2567G>T	p.Arg856Leu	missense	Exon 23 of 27	NP_001317140.1	F5GY88
	MED24	NM_001079518.2		c.2471G>T	p.Arg824Leu	missense	Exon 21 of 25	NP_001072986.1	O75448-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED24	ENST00000394128.7	TSL:1 MANE Select	c.2510G>T	p.Arg837Leu	missense	Exon 22 of 26	ENSP00000377686.2	O75448-1
	MED24	ENST00000394126.5	TSL:1	c.2585G>T	p.Arg862Leu	missense	Exon 21 of 25	ENSP00000377684.1	A0A0B4J1W0
	MED24	ENST00000422942.6	TSL:1	c.290G>T	p.Arg97Leu	missense	Exon 3 of 7	ENSP00000393464.2	B9TX62

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457470 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724580

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 85276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110264

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.61	P
Vest4		0.72
MutPred		0.53		Gain of ubiquitination at K834 (P = 0.0357)
MVP		0.75
MPC		1.2
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.41
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137866788; hg19: chr17-38178660;