chr17-40019895-G-A

Variant names:

• chr17-40019895-G-A
• rs748099423
• NM_014815.4:c.2743C>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.2743C>T​(p.Arg915Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000825 in 1,575,500 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: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: MED24 NM_014815.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 3 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=0.25201663).

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.2743C>T	p.Arg915Cys	missense	Exon 25 of 26	NP_055630.2
	MED24	NM_001330211.2		c.2800C>T	p.Arg934Cys	missense	Exon 26 of 27	NP_001317140.1	F5GY88
	MED24	NM_001079518.2		c.2704C>T	p.Arg902Cys	missense	Exon 24 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.2743C>T	p.Arg915Cys	missense	Exon 25 of 26	ENSP00000377686.2	O75448-1
	MED24	ENST00000394126.5	TSL:1	c.2818C>T	p.Arg940Cys	missense	Exon 24 of 25	ENSP00000377684.1	A0A0B4J1W0
	MED24	ENST00000422942.6	TSL:1	c.652C>T	p.Arg218Cys	missense	Exon 6 of 7	ENSP00000393464.2	B9TX62

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000484 AC: 9 AN: 185832 AF XY: 0.0000202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000512

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000857 AC: 122 AN: 1423228 Hom.: 0 Cov.: 33 AF XY: 0.0000710 AC XY: 50 AN XY: 704136

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.000130 AC: 5 AN: 38408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37902

South Asian (SAS) AF: 0.00 AC: 0 AN: 81442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.000101 AC: 110 AN: 1091728

Other (OTH) AF: 0.000102 AC: 6 AN: 58980

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000167 AC: 2

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	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Benign	0.68
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.097
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.022	B
Vest4		0.37
MutPred		0.35		Loss of disorder (P = 0.0167)
MVP		0.49
MPC		0.82
ClinPred		0.33	T
GERP RS		1.8
Varity_R		0.21
gMVP		0.32
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs748099423; hg19: chr17-38176148; COSMIC: COSV56641716; COSMIC: COSV56641716;