Variant 19-868127-G-A 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.2608C>T(p.His870Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,610,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

MED16
NM_005481.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.40

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=0.009125531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED16	NM_005481.3 linkuse as main transcript	c.2608C>T	p.His870Tyr	missense_variant	16/16	ENST00000325464.6	NP_005472.2	Q9Y2X0-1
MED16	XM_017026120.3 linkuse as main transcript	c.2401C>T	p.His801Tyr	missense_variant	15/15		XP_016881609.1
MED16	XM_047438010.1 linkuse as main transcript	c.*246C>T		3_prime_UTR_variant	14/14		XP_047293966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED16	ENST00000325464.6 linkuse as main transcript	c.2608C>T	p.His870Tyr	missense_variant	16/16	5	NM_005481.3	ENSP00000325612.1		Q9Y2X0-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000829

AC:

AN:

241144

Hom.:

AF XY:

0.0000760

AC XY:

AN XY:

131564

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000936

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1458560

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

725618

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000447

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00162

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000484

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

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

Apr 13, 2022

The c.2608C>T (p.H870Y) alteration is located in exon 16 (coding exon 15) of the MED16 gene. This alteration results from a C to T substitution at nucleotide position 2608, causing the histidine (H) at amino acid position 870 to be replaced by a tyrosine (Y). 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

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.9

DANN

Benign

0.77

DEOGEN2

Benign

0.029

T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.38

.;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.10

.;N;.

REVEL

Benign

0.051

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.020

D;D;T

Polyphen

0.023

B;B;.

Vest4

0.16

MVP

0.030

ClinPred

0.016

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.076

gMVP

0.23

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