rs776426730

Variant names:

• chr17-40019536-G-A
• rs776426730
• NM_014815.4:c.2963C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014815.4(MED24):​c.2963C>T​(p.Ala988Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MED24 NM_014815.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20782456).

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.2963C>T	p.Ala988Val	missense	Exon 26 of 26	NP_055630.2
	MED24	NM_001330211.2		c.3020C>T	p.Ala1007Val	missense	Exon 27 of 27	NP_001317140.1	F5GY88
	MED24	NM_001079518.2		c.2924C>T	p.Ala975Val	missense	Exon 25 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.2963C>T	p.Ala988Val	missense	Exon 26 of 26	ENSP00000377686.2	O75448-1
	MED24	ENST00000394126.5	TSL:1	c.3038C>T	p.Ala1013Val	missense	Exon 25 of 25	ENSP00000377684.1	A0A0B4J1W0
	MED24	ENST00000422942.6	TSL:1	c.872C>T	p.Ala291Val	missense	Exon 7 of 7	ENSP00000393464.2	B9TX62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250132 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459486 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111580

Other (OTH) AF: 0.0000166 AC: 1 AN: 60236

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Benign	0.82
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		9.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.29
Sift	Benign	0.36	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.69
MutPred		0.37		Loss of disorder (P = 0.0815)
MVP		0.51
MPC		0.43
ClinPred		0.21	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.42
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs776426730; hg19: chr17-38175789;