Genetic Variant MED4:p.Arg72Gln (chr13-48086430-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014166.4(MED4):c.215G>A(p.Arg72Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

MED4
NM_014166.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11218807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED4	NM_014166.4 link	c.215G>A	p.Arg72Gln	missense_variant	Exon 3 of 7	ENST00000258648.7	NP_054885.1	Q9NPJ6-1A0A024RDY7
MED4	NM_001270629.2 link	c.77G>A	p.Arg26Gln	missense_variant	Exon 3 of 7		NP_001257558.1	Q9NPJ6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED4	ENST00000258648.7 link	c.215G>A	p.Arg72Gln	missense_variant	Exon 3 of 7	1	NM_014166.4	ENSP00000258648.2	Q9NPJ6-1
MED4	ENST00000417167.2 link	c.149G>A	p.Arg50Gln	missense_variant	Exon 4 of 8	5		ENSP00000413595.1	Q5T911
MED4	ENST00000378586.5 link	c.77G>A	p.Arg26Gln	missense_variant	Exon 3 of 7	2		ENSP00000367849.1	Q9NPJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251116

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461426

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215G>A (p.R72Q) alteration is located in exon 3 (coding exon 3) of the MED4 gene. This alteration results from a G to A substitution at nucleotide position 215, causing the arginine (R) at amino acid position 72 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;.;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.0059

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.069

T;T;T

Sift4G

Benign

0.10

T;T;.

Polyphen

0.90

P;.;.

Vest4

0.58

MutPred

0.59

Gain of catalytic residue at D73 (P = 0.0119);.;.;

MVP

0.76

MPC

0.64

ClinPred

0.098

GERP RS

5.3

Varity_R

0.15

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over