chr11-93784567-G-T

Variant names:

• chr11-93784567-G-T
• rs1320047535
• NM_004268.5:c.54G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004268.5(MED17):​c.54G>T​(p.Gln18His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q18Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MED17 NM_004268.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.28
• Publications: 0 publications found

Genes affected

MED17 (HGNC:2375): (mediator complex subunit 17) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. [provided by RefSeq, Jul 2008]

ENSG00000284057 (HGNC:):

TAF1D (HGNC:28759): (TATA-box binding protein associated factor, RNA polymerase I subunit D) TAF1D is a member of the SL1 complex, which includes TBP (MIM 600075) and TAF1A (MIM 604903), TAF1B (MIM 604904), and TAF1C (MIM 604905), and plays a role in RNA polymerase I transcription (Wang et al., 2004 [PubMed 15520167]; Gorski et al., 2007 [PubMed 17318177]).[supplied by OMIM, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED17	NM_004268.5	c.54G>T	p.Gln18His	missense_variant	Exon 1 of 12	ENST00000251871.9	NP_004259.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED17	ENST00000251871.9	c.54G>T	p.Gln18His	missense_variant	Exon 1 of 12	1	NM_004268.5	ENSP00000251871.3
ENSG00000284057	ENST00000638767.1	c.676-61G>T		intron_variant	Intron 7 of 18	5		ENSP00000492220.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460142 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726342

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

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

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;T;D;T;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
PhyloP100		4.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;.;N;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.018	D;.;D;.;.;.
Sift4G	Uncertain	0.012	D;.;D;.;.;.
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.46
MutPred		0.80		Loss of ubiquitination at K17 (P = 0.0896);Loss of ubiquitination at K17 (P = 0.0896);Loss of ubiquitination at K17 (P = 0.0896);Loss of ubiquitination at K17 (P = 0.0896);Loss of ubiquitination at K17 (P = 0.0896);Loss of ubiquitination at K17 (P = 0.0896);
MVP		0.62
MPC		0.88
ClinPred		0.98	D
GERP RS		5.8
PromoterAI		-0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.49
gMVP		0.82
Mutation Taster		=26/74	disease causing

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: rs1320047535; hg19: chr11-93517733;