17-40021963-G-T

Variant names:

• chr17-40021963-G-T
• rs377258028
• NM_014815.4:c.2615C>A

Variant summary

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

The NM_014815.4(MED24):​c.2615C>A​(p.Ser872*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED24 NM_014815.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.77
• Publications: 0 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.2615C>A	p.Ser872*	stop_gained	Exon 23 of 26	NP_055630.2
	MED24	NM_001330211.2		c.2672C>A	p.Ser891*	stop_gained	Exon 24 of 27	NP_001317140.1	F5GY88
	MED24	NM_001079518.2		c.2576C>A	p.Ser859*	stop_gained	Exon 22 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.2615C>A	p.Ser872*	stop_gained	Exon 23 of 26	ENSP00000377686.2	O75448-1
	MED24	ENST00000394126.5	TSL:1	c.2690C>A	p.Ser897*	stop_gained	Exon 22 of 25	ENSP00000377684.1	A0A0B4J1W0
	MED24	ENST00000422942.6	TSL:1	c.395C>A	p.Ser132*	stop_gained	Exon 4 of 7	ENSP00000393464.2	B9TX62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449002 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720108

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.00 AC: 0 AN: 84824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105482

Other (OTH) AF: 0.00 AC: 0 AN: 59830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.61	D
PhyloP100		9.8
Vest4		0.41
ClinPred		1.0	D
GERP RS		3.2

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: rs377258028; hg19: chr17-38178216;