17-40022663-G-T

Variant names:

• chr17-40022663-G-T
• rs535594488
• NM_014815.4:c.2414C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014815.4(MED24):​c.2414C>A​(p.Pro805Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. P805L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MED24 NM_014815.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39398405).

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.2414C>A	p.Pro805Gln	missense	Exon 21 of 26	NP_055630.2
	MED24	NM_001330211.2		c.2471C>A	p.Pro824Gln	missense	Exon 22 of 27	NP_001317140.1	F5GY88
	MED24	NM_001079518.2		c.2375C>A	p.Pro792Gln	missense	Exon 20 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.2414C>A	p.Pro805Gln	missense	Exon 21 of 26	ENSP00000377686.2	O75448-1
	MED24	ENST00000394126.5	TSL:1	c.2489C>A	p.Pro830Gln	missense	Exon 20 of 25	ENSP00000377684.1	A0A0B4J1W0
	MED24	ENST00000422942.6	TSL:1	c.194C>A	p.Pro65Gln	missense	Exon 2 of 7	ENSP00000393464.2	B9TX62

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.75
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		10
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.44	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.41		Loss of catalytic residue at P804 (P = 0.016)
MVP		0.53
MPC		1.0
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		-0.00040	Neutral
Varity_R		0.12
gMVP		0.44

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: rs535594488; hg19: chr17-38178916;