17-78049582-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142640.2(TNRC6C):c.1150G>A(p.Ala384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: TNRC6C NM_001142640.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.696

Genes affected

TNRC6C (HGNC:29318): (trinucleotide repeat containing adaptor 6C) Predicted to enable RNA binding activity. Involved in gene silencing by miRNA; positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; and positive regulation of nuclear-transcribed mRNA poly(A) tail shortening. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.038744092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNRC6C	NM_001142640.2	c.1150G>A	p.Ala384Thr	missense_variant	5/23	ENST00000696270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNRC6C	ENST00000696270.1	c.1150G>A	p.Ala384Thr	missense_variant	5/23		NM_001142640.2	P4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 249136 Hom.: 1 AF XY: 0.000178 AC XY: 24 AN XY: 135158

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461608 Hom.: 1 Cov.: 33 AF XY: 0.000147 AC XY: 107 AN XY: 727084

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74460

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.520G>A (p.A174T) alteration is located in exon 4 (coding exon 1) of the TNRC6C gene. This alteration results from a G to A substitution at nucleotide position 520, causing the alanine (A) at amino acid position 174 to be replaced by a threonine (T). 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	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	21
Dann	Benign	0.80
DEOGEN2	Benign	0.0090	T;.;T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;.;.;D;D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
Polyphen		0.52, 0.0070	.;P;B;B;P
Vest4		0.12, 0.11, 0.11, 0.12
MVP		0.093
MPC		0.28
ClinPred		0.0085	T
GERP RS		-0.10
Varity_R		0.023
gMVP		0.43

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: rs200226260; hg19: chr17-76045663; COSMIC: COSV56941261; COSMIC: COSV56941261;