19-871054-C-A

Variant names:

• chr19-871054-C-A
• rs1188100993
• NM_005481.3:c.2298G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005481.3(MED16):​c.2298G>T​(p.Gln766His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,544,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MED16 NM_005481.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06361541).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005481.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED16	NM_005481.3	MANE Select	c.2298G>T	p.Gln766His	missense	Exon 13 of 16	NP_005472.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED16	ENST00000325464.6	TSL:5 MANE Select	c.2298G>T	p.Gln766His	missense	Exon 13 of 16	ENSP00000325612.1	Q9Y2X0-1
	MED16	ENST00000312090.10	TSL:1	c.2355G>T	p.Gln785His	missense	Exon 14 of 16	ENSP00000308528.4	Q9Y2X0-3
	MED16	ENST00000395808.7	TSL:1	c.2298G>T	p.Gln766His	missense	Exon 13 of 15	ENSP00000379153.1	Q9Y2X0-2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000960 AC: 14 AN: 145796 AF XY: 0.000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000115 AC: 16 AN: 1391980 Hom.: 0 Cov.: 33 AF XY: 0.0000146 AC XY: 10 AN XY: 685382

African (AFR) AF: 0.00 AC: 0 AN: 31418

American (AMR) AF: 0.00 AC: 0 AN: 35546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.000394 AC: 14 AN: 35542

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5016

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075074

Other (OTH) AF: 0.00 AC: 0 AN: 57588

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.096
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.061
Sift	Benign	0.041	D
Sift4G	Benign	0.14	T
Polyphen		0.79	P
Vest4		0.19
MutPred		0.41		Gain of glycosylation at T764 (P = 0.0632)
MVP		0.32
ClinPred		0.081	T
GERP RS		1.6
PromoterAI		0.0041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.56
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1188100993; hg19: chr19-871054;