17-40022693-G-A

Variant names:

• chr17-40022693-G-A
• rs1982178235
• NM_014815.4:c.2384C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014815.4(MED24):​c.2384C>T​(p.Ser795Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MED24 NM_014815.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED24	NM_014815.4	c.2384C>T	p.Ser795Phe	missense_variant	Exon 21 of 26	ENST00000394128.7	NP_055630.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED24	ENST00000394128.7	c.2384C>T	p.Ser795Phe	missense_variant	Exon 21 of 26	1	NM_014815.4	ENSP00000377686.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461688 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2384C>T (p.S795F) alteration is located in exon 21 (coding exon 20) of the MED24 gene. This alteration results from a C to T substitution at nucleotide position 2384, causing the serine (S) at amino acid position 795 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;.;D;.;.;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N;.;D;D;D;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;.;D;D;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		0.99, 0.99	.;D;D;D;.;.;.
Vest4		0.69
MutPred		0.33		.;.;Loss of disorder (P = 8e-04);.;.;.;.;
MVP		0.92
MPC		1.1
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1982178235; hg19: chr17-38178946; COSMIC: COSV56642047; COSMIC: COSV56642047;