16-24777324-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014494.4(TNRC6A):c.555T>A(p.Asn185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,612,918 control chromosomes in the GnomAD database, including 28,634 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (2734 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25900 hom.)
• Consequence: TNRC6A NM_014494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.846

Genes affected

TNRC6A (HGNC:11969): (trinucleotide repeat containing adaptor 6A) This gene encodes a member of the trinucleotide repeat containing 6 protein family. The protein functions in post-transcriptional gene silencing through the RNA interference (RNAi) and microRNA pathways. The protein associates with messenger RNAs and Argonaute proteins in cytoplasmic bodies known as GW-bodies or P-bodies. Inhibiting expression of this gene delocalizes other GW-body proteins and impairs RNAi and microRNA-induced gene silencing. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.302199E-4).
• BP6: Variant 16-24777324-T-A is Benign according to our data. Variant chr16-24777324-T-A is described in ClinVar as [Benign]. Clinvar id is 1279086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNRC6A	NM_014494.4	c.555T>A	p.Asn185Lys	missense_variant	5/25	ENST00000395799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNRC6A	ENST00000395799.8	c.555T>A	p.Asn185Lys	missense_variant	5/25	5	NM_014494.4	A2
TNRC6A	ENST00000491718.5	c.78T>A	p.Asn26Lys	missense_variant, NMD_transcript_variant	1/22	1
TNRC6A	ENST00000315183.11	c.555T>A	p.Asn185Lys	missense_variant	5/24	5		P4

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28315 AN: 152002 Hom.: 2735 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.172 AC: 42857 AN: 248664 Hom.: 3852 AF XY: 0.171 AC XY: 23142 AN XY: 135022

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.186 AC: 272146 AN: 1460798 Hom.: 25900 Cov.: 35 AF XY: 0.185 AC XY: 134267 AN XY: 726750

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.186 AC: 28310 AN: 152120 Hom.: 2734 Cov.: 32 AF XY: 0.180 AC XY: 13375 AN XY: 74374

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.197

Alfa AF: 0.193 Hom.: 2173

Bravo AF: 0.189

TwinsUK AF: 0.195 AC: 724

ALSPAC AF: 0.196 AC: 754

ESP6500AA AF: 0.189 AC: 770

ESP6500EA AF: 0.187 AC: 1574

ExAC AF: 0.174 AC: 21086

Asia WGS AF: 0.139 AC: 486 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2021

- -

Epilepsy, familial adult myoclonic, 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.59
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.00093	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.089
Sift	Benign	0.090	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0	.;B
Vest4		0.082
MutPred		0.075		Gain of ubiquitination at N185 (P = 0.0029);Gain of ubiquitination at N185 (P = 0.0029);
MPC		0.10
ClinPred		0.0025	T
GERP RS		2.4
Varity_R		0.049
gMVP		0.14

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

Other links and lift over

dbSNP: rs11639856; hg19: chr16-24788645; COSMIC: COSV59361345; COSMIC: COSV59361345;