Variant 19-871110-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005481.3(MED16):c.2242C>T(p.Leu748Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,396,360 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MED16
NM_005481.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.996

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:

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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=0.17481458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED16	NM_005481.3 linkuse as main transcript	c.2242C>T	p.Leu748Phe	missense_variant	13/16	ENST00000325464.6	NP_005472.2	Q9Y2X0-1
MED16	XM_017026120.3 linkuse as main transcript	c.2035C>T	p.Leu679Phe	missense_variant	12/15		XP_016881609.1
MED16	XM_047438010.1 linkuse as main transcript	c.2035C>T	p.Leu679Phe	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.2242C>T	p.Leu748Phe	missense_variant	13/16	5	NM_005481.3	ENSP00000325612.1		Q9Y2X0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1396360

Hom.:

Cov.:

AF XY:

0.00000871

AC XY:

AN XY:

688512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000176

Gnomad4 OTH exome

AF:

0.0000518

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000146

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 02, 2023

The c.2242C>T (p.L748F) alteration is located in exon 13 (coding exon 12) of the MED16 gene. This alteration results from a C to T substitution at nucleotide position 2242, causing the leucine (L) at amino acid position 748 to be replaced by a phenylalanine (F). 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

0.23

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

.;.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.92

D;D;.;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.;M;M

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.9

N;N;.;N

REVEL

Benign

0.13

Sift

Benign

0.039

D;D;.;D

Sift4G

Benign

0.10

T;D;T;T

Polyphen

0.67, 0.86

.;P;P;P

Vest4

0.25

MutPred

0.19

Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.51

ClinPred

0.59

GERP RS

-1.8

Varity_R

0.12

gMVP

0.58

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