11-93784504-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_004268.5(MED17):​c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,592,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

MED17
NM_004268.5 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: 0.684
Variant links:
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000276 (42/152292) while in subpopulation NFE AF= 0.000515 (35/68022). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED17NM_004268.5 linkc.-10C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 12 ENST00000251871.9 NP_004259.3 Q9NVC6-1
MED17NM_004268.5 linkc.-10C>T 5_prime_UTR_variant Exon 1 of 12 ENST00000251871.9 NP_004259.3 Q9NVC6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED17ENST00000251871 linkc.-10C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 12 1 NM_004268.5 ENSP00000251871.3 Q9NVC6-1
MED17ENST00000251871 linkc.-10C>T 5_prime_UTR_variant Exon 1 of 12 1 NM_004268.5 ENSP00000251871.3 Q9NVC6-1
ENSG00000284057ENST00000638767.1 linkc.676-124C>T intron_variant Intron 7 of 18 5 ENSP00000492220.1 A0A1W2PRB8

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152174
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000514
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000365
AC:
88
AN:
241058
Hom.:
0
AF XY:
0.000304
AC XY:
40
AN XY:
131750
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000591
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000736
Gnomad NFE exome
AF:
0.000651
Gnomad OTH exome
AF:
0.000170
GnomAD4 exome
AF:
0.000248
AC:
357
AN:
1440252
Hom.:
1
Cov.:
29
AF XY:
0.000217
AC XY:
155
AN XY:
712864
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000455
Gnomad4 ASJ exome
AF:
0.0000388
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000611
Gnomad4 NFE exome
AF:
0.000276
Gnomad4 OTH exome
AF:
0.000337
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152292
Hom.:
0
Cov.:
33
AF XY:
0.000255
AC XY:
19
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.000515
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000690
Hom.:
0
Bravo
AF:
0.000200

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

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

- -

MED17-related disorder Benign:1
Apr 10, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
12
DANN
Benign
0.92
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199995347; hg19: chr11-93517670; API