rs2848477

Variant names:

• chr11-93784720-G-C
• rs2848477
• NM_004268.5:c.207G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-93784720-G-C
• chr11-93784720-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:9
• Conservation: PhyloP100: 0.209
• Publications: 33 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]

MED17 Gene-Disease associations (from GenCC):

• infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ENSG00000284057 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004268.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED17	NM_004268.5	MANE Select	c.207G>C	p.Glu69Asp	missense	Exon 1 of 12	NP_004259.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED17	ENST00000251871.9	TSL:1 MANE Select	c.207G>C	p.Glu69Asp	missense	Exon 1 of 12	ENSP00000251871.3	Q9NVC6-1
	ENSG00000284057	ENST00000638767.1	TSL:5	c.768G>C	p.Glu256Asp	missense	Exon 8 of 19	ENSP00000492220.1	A0A1W2PRB8
	MED17	ENST00000639724.1	TSL:5	c.207G>C	p.Glu69Asp	missense	Exon 1 of 11	ENSP00000492625.1	A0A1W2PS27

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

GnomAD2 exomes AF: 0.646 AC: 97056 AN: 150320 AF XY: 0.642

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 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

African (AFR) AF: 0.324 AC: 10391 AN: 32100

American (AMR) AF: 0.780 AC: 27867 AN: 35740

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 14719 AN: 25166

East Asian (EAS) AF: 0.763 AC: 27779 AN: 36402

South Asian (SAS) AF: 0.598 AC: 47584 AN: 79528

European-Finnish (FIN) AF: 0.658 AC: 27254 AN: 41398

Middle Eastern (MID) AF: 0.589 AC: 3146 AN: 5342

European-Non Finnish (NFE) AF: 0.629 AC: 679936 AN: 1080686

Other (OTH) AF: 0.614 AC: 35668 AN: 58076

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

African (AFR) AF: 0.334 AC: 13821 AN: 41426

American (AMR) AF: 0.704 AC: 10743 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2046 AN: 3468

East Asian (EAS) AF: 0.749 AC: 3840 AN: 5128

South Asian (SAS) AF: 0.596 AC: 2872 AN: 4822

European-Finnish (FIN) AF: 0.668 AC: 7019 AN: 10510

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42527 AN: 67826

Other (OTH) AF: 0.582 AC: 1231 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.21
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.19
Sift	Benign	0.87	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.40		Gain of helix (P = 0.027)
MPC		0.25
ClinPred		0.0029	T
GERP RS		1.7
PromoterAI		0.0011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.24
Mutation Taster		=88/12	polymorphism (auto)

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