rs35313315

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004268.5(MED17):c.1071T>A(p.Phe357Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,832 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0080 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 11 hom. )

Consequence

MED17
NM_004268.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0160

Publications

4 publications found

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]

MED17 Gene-Disease associations (from GenCC):

infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

MED17 links:

ENSG00000284057 (HGNC:):

ENSG00000284057 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019546747).

BP6

Variant 11-93796468-T-A is Benign according to our data. Variant chr11-93796468-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129596.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00803 (1223/152354) while in subpopulation AFR AF = 0.027 (1121/41582). AF 95% confidence interval is 0.0256. There are 18 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED17	NM_004268.5 link	c.1071T>A	p.Phe357Leu	missense_variant	Exon 7 of 12	ENST00000251871.9	NP_004259.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED17	ENST00000251871.9 link	c.1071T>A	p.Phe357Leu	missense_variant	Exon 7 of 12	1	NM_004268.5	ENSP00000251871.3
ENSG00000284057	ENST00000638767.1 link	c.1632T>A	p.Phe544Leu	missense_variant	Exon 14 of 19	5		ENSP00000492220.1

Frequencies

GnomAD3 genomes

AF:

0.00803

AC:

1222

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00221

AC:

556

AN:

251302

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.0288

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000908

AC:

1327

AN:

1461478

Hom.:

Cov.:

AF XY:

0.000817

AC XY:

594

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0312

AC:

1044

AN:

33466

American (AMR)

AF:

0.00197

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000819

AC:

AN:

1111654

Other (OTH)

AF:

0.00151

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00803

AC:

1223

AN:

152354

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0270

AC:

1121

AN:

41582

American (AMR)

AF:

0.00490

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68036

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00951

ESP6500AA

AF:

0.0298

AC:

131

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00254

AC:

309

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Dec 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

Benign:2

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.054

.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.;.;.

PhyloP100

-0.016

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.26

.;N;.;.;.

REVEL

Benign

0.042

Sift

Benign

0.47

.;T;.;.;.

Sift4G

Benign

0.49

.;T;.;.;.

Polyphen

0.0010

.;B;.;.;.

Vest4

0.11

MutPred

0.24

.;Loss of methylation at K356 (P = 0.0692);Loss of methylation at K356 (P = 0.0692);.;Loss of methylation at K356 (P = 0.0692);

MVP

0.20

MPC

0.32

ClinPred

0.0032

GERP RS

0.092

Varity_R

0.057

gMVP

0.14

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over