11-93784521-G-T

Variant names:

• chr11-93784521-G-T
• rs1320244785
• NM_004268.5:c.8G>T

Variant summary

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

The NM_004268.5(MED17):​c.8G>T​(p.Gly3Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G3G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED17 NM_004268.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.02
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED17	NM_004268.5	c.8G>T	p.Gly3Val	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.8G>T	p.Gly3Val	missense_variant	Exon 1 of 12	1	NM_004268.5	ENSP00000251871.3
ENSG00000284057	ENST00000638767.1	c.676-107G>T		intron_variant	Intron 7 of 18	5		ENSP00000492220.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449978 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 2 AN XY: 719210

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104404

Other (OTH) AF: 0.00 AC: 0 AN: 59790

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8G>T (p.G3V) alteration is located in exon 1 (coding exon 1) of the MED17 gene. This alteration results from a G to T substitution at nucleotide position 8, causing the glycine (G) at amino acid position 3 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly Uncertain:1

Apr 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
PhyloP100		9.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.48	N;.;N;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D;.;D;.;.;.
Sift4G	Benign	0.072	T;.;D;.;.;.
Polyphen		0.46	P;.;.;.;.;.
Vest4		0.65
MutPred		0.53		Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);
MVP		0.77
MPC		0.89
ClinPred		0.98	D
GERP RS		4.8
PromoterAI		-0.00040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.78
Mutation Taster		=43/57	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: rs1320244785; hg19: chr11-93517687;