rs267607232

Positions:

• chr11-93796509-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004268.5(MED17):​c.1112T>C​(p.Leu371Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED17 NM_004268.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.94

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 11-93796509-T-C is Pathogenic according to our data. Variant chr11-93796509-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED17	NM_004268.5	c.1112T>C	p.Leu371Pro	missense_variant	7/12	ENST00000251871.9	NP_004259.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED17	ENST00000251871.9	c.1112T>C	p.Leu371Pro	missense_variant	7/12	1	NM_004268.5	ENSP00000251871.3
ENSG00000284057	ENST00000638767.1	c.1673T>C	p.Leu558Pro	missense_variant	14/19	5		ENSP00000492220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 12, 2010	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Published functional studies demonstrate L371P results in a functionally inactive protein (Kaufmann et al., 2010; Eyboulet et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21840410, 33756211, 25446406, 33649303, 26240385, 20950787) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 371 of the MED17 protein (p.Leu371Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with infantile cerebral and cerebellar atrophy (PMID: 20950787). ClinVar contains an entry for this variant (Variation ID: 18441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MED17 protein function. Experimental studies have shown that this missense change affects MED17 function (PMID: 20950787, 26240385). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	.;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	.;D;.;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	.;D;.;.;.
Sift4G	Uncertain	0.0020	.;D;.;.;.
Polyphen		1.0	.;D;.;.;.
Vest4		0.98
MutPred		0.81		.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);
MVP		0.88
MPC		1.2
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.88
gMVP		0.88

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

Other links and lift over

dbSNP: rs267607232; hg19: chr11-93529675;