rs2848477

chr11-93784720-G-Cchr11-93784720-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004268.5(MED17):c.207G>C(p.Glu69Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,546,188 control chromosomes in the GnomAD database, including 302,643 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25275 hom., cov: 33)
  • Exomes 𝑓: 0.63 (277368 hom.)
• Consequence: MED17 NM_004268.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.209

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3689065E-6).
• BP6: Variant 11-93784720-G-C is Benign according to our data. Variant chr11-93784720-G-C is described in ClinVar as [Benign]. Clinvar id is 129601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-93784720-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED17	NM_004268.5	c.207G>C	p.Glu69Asp	missense_variant	1/12	ENST00000251871.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED17	ENST00000251871.9	c.207G>C	p.Glu69Asp	missense_variant	1/12	1	NM_004268.5	P1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84751 AN: 151632 Hom.: 25262 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.585

GnomAD3 exomes AF: 0.646 AC: 97056 AN: 150320 Hom.: 32277 AF XY: 0.642 AC XY: 51847 AN XY: 80760

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.583

Gnomad EAS exome AF: 0.751

Gnomad SAS exome AF: 0.596

Gnomad FIN exome AF: 0.673

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.627 AC: 874344 AN: 1394438 Hom.: 277368 Cov.: 76 AF XY: 0.627 AC XY: 431532 AN XY: 688248

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.780

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.598

Gnomad4 FIN exome AF: 0.658

Gnomad4 NFE exome AF: 0.629

Gnomad4 OTH exome AF: 0.614

GnomAD4 genome AF: 0.559 AC: 84790 AN: 151750 Hom.: 25275 Cov.: 33 AF XY: 0.564 AC XY: 41835 AN XY: 74134

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.749

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.668

Gnomad4 NFE AF: 0.627

Gnomad4 OTH AF: 0.582

Alfa AF: 0.601 Hom.: 8245

Bravo AF: 0.554

TwinsUK AF: 0.634 AC: 2351

ALSPAC AF: 0.634 AC: 2444

ESP6500AA AF: 0.369 AC: 1525

ESP6500EA AF: 0.642 AC: 5300

ExAC AF: 0.544 AC: 49987

Asia WGS AF: 0.611 AC: 2122 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 28, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	10
Dann	Benign	0.69
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.22	T;T;T;T;T;T;T
MetaRNN	Benign	0.0000024	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.70	T
Polyphen		0.0	.;B;.;.;.;.;.
Vest4		0.018
MutPred		0.40		.;Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MPC		0.25
ClinPred		0.0029	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.24

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: rs2848477; hg19: chr11-93517886; COSMIC: COSV52599620; COSMIC: COSV52599620;