Genetic Variant MED4:p.Asp253Glu (chr13-48077193-A-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014166.4(MED4):c.759T>A(p.Asp253Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,608,846 control chromosomes in the GnomAD database, including 16 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 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 15 hom. )

Consequence

MED4
NM_014166.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.823

Publications

5 publications found

Variant links:

Genes affected

MED4 (HGNC:17903): (mediator complex subunit 4) This gene encodes a component of the Mediator complex. The Mediator complex interacts with DNA-binding gene-specific transcription factors to modulate transcription by RNA polymerase II. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

MED4 links:

MED4-AS1 (HGNC:39213): (MED4 antisense RNA 1)

MED4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00830999).

BP6

Variant 13-48077193-A-T is Benign according to our data. Variant chr13-48077193-A-T is described in ClinVar as Benign. ClinVar VariationId is 773271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED4	NM_014166.4 link	c.759T>A	p.Asp253Glu	missense_variant	Exon 7 of 7	ENST00000258648.7	NP_054885.1	Q9NPJ6-1A0A024RDY7
MED4	NM_001270629.2 link	c.621T>A	p.Asp207Glu	missense_variant	Exon 7 of 7		NP_001257558.1	Q9NPJ6-2
MED4-AS1	NR_046511.1 link	n.57A>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED4	ENST00000258648.7 link	c.759T>A	p.Asp253Glu	missense_variant	Exon 7 of 7	1	NM_014166.4	ENSP00000258648.2		Q9NPJ6-1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

457

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00303

AC:

741

AN:

244486

AF XY:

0.00294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00395

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00285

Gnomad OTH exome

AF:

0.00420

GnomAD4 exome

AF:

0.00251

AC:

3661

AN:

1456560

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1827

AN XY:

724612

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33010

American (AMR)

AF:

0.00129

AC:

AN:

43476

Ashkenazi Jewish (ASJ)

AF:

0.00442

AC:

115

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39220

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85266

European-Finnish (FIN)

AF:

0.0145

AC:

774

AN:

53324

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00233

AC:

2582

AN:

1110334

Other (OTH)

AF:

0.00209

AC:

126

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

173

345

518

690

863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00300

AC:

457

AN:

152286

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

257

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41568

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00341

AC:

232

AN:

68010

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00276

Hom.:

Bravo

AF:

0.00169

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00282

AC:

342

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.048

T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.58

N;.;.

PhyloP100

0.82

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.27

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.35

T;T;.

Polyphen

0.0020

B;.;.

Vest4

0.31

MutPred

0.51

Loss of stability (P = 0.1053);.;.;

MVP

0.41

MPC

0.33

ClinPred

0.032

GERP RS

2.0

Varity_R

0.053

gMVP

0.18

Mutation Taster

=98/2

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