Variant 19-871106-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005481.3(MED16):c.2246G>A(p.Arg749His) variant causes a missense change. The variant allele was found at a frequency of 0.0000497 in 1,548,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

MED16
NM_005481.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

Variant links:

Genes affected

MED16 (HGNC:17556): (mediator complex subunit 16) Enables thyroid hormone receptor binding activity and transcription coactivator activity. Involved in positive regulation of transcription initiation from RNA polymerase II promoter. Located in membrane. Part of mediator complex. [provided by Alliance of Genome Resources, Apr 2022]

MED16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047286272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MED16	NM_005481.3 linkuse as main transcript	c.2246G>A	p.Arg749His	missense_variant	13/16	ENST00000325464.6	NP_005472.2
MED16	XM_017026120.3 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	12/15		XP_016881609.1
MED16	XM_047438010.1 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	12/14		XP_047293966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED16	ENST00000325464.6 linkuse as main transcript	c.2246G>A	p.Arg749His	missense_variant	13/16	5	NM_005481.3	ENSP00000325612		Q9Y2X0-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000300

AC:

AN:

146614

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

78196

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00380

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000661

Gnomad NFE exome

AF:

0.0000376

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1396396

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

688542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00115

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000453

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.2246G>A (p.R749H) alteration is located in exon 13 (coding exon 12) of the MED16 gene. This alteration results from a G to A substitution at nucleotide position 2246, causing the arginine (R) at amino acid position 749 to be replaced by a histidine (H). 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

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

.;.;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;N;.;N

REVEL

Benign

0.24

Sift

Benign

0.030

D;D;.;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.99, 0.99

.;D;D;D

Vest4

0.70

MutPred

0.49

Gain of ubiquitination at K745 (P = 0.0556);.;Gain of ubiquitination at K745 (P = 0.0556);Gain of ubiquitination at K745 (P = 0.0556);

MVP

0.16

ClinPred

0.18

GERP RS

3.0

Varity_R

0.11

gMVP

0.56

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