rs9611280

Positions:

• chr22-40156115-G-A
• chr22-40156115-G-T

Variant summary

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

The ENST00000402203.5(TNRC6B):​c.46G>A​(p.Val16Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 1,576,008 control chromosomes in the GnomAD database, including 8,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (481 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7567 hom.)
• Consequence: TNRC6B ENST00000402203.5 missense, splice_region
• Scores: Splicing: ADA: 0.01321
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.07

Genes affected

TNRC6B (HGNC:29190): (trinucleotide repeat containing adaptor 6B) Enables RNA binding activity. Involved in regulation of gene expression. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm. Implicated in subserous uterine fibroid and uterine fibroid. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013531148).
• BP6: Variant 22-40156115-G-A is Benign according to our data. Variant chr22-40156115-G-A is described in ClinVar as [Benign]. Clinvar id is 1315562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNRC6B	NM_001024843.2	c.46G>A	p.Val16Met	missense_variant, splice_region_variant	4/24		NP_001020014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000402203.5	c.46G>A	p.Val16Met	missense_variant, splice_region_variant	4/24	1		ENSP00000384795	A2
TNRC6B	ENST00000301923.13	c.46G>A	p.Val16Met	missense_variant, splice_region_variant	4/24	5		ENSP00000306759	A2
TNRC6B	ENST00000441751.5	c.46G>A	p.Val16Met	missense_variant, splice_region_variant	4/4	5		ENSP00000397491

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10499 AN: 152174 Hom.: 481 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0683

GnomAD3 exomes AF: 0.0677 AC: 13201 AN: 194968 Hom.: 629 AF XY: 0.0675 AC XY: 7001 AN XY: 103642

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.000139

Gnomad SAS exome AF: 0.0457

Gnomad FIN exome AF: 0.0645

Gnomad NFE exome AF: 0.0976

Gnomad OTH exome AF: 0.0729

GnomAD4 exome AF: 0.0981 AC: 139732 AN: 1423716 Hom.: 7567 Cov.: 31 AF XY: 0.0962 AC XY: 67772 AN XY: 704206

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.0438

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0000525

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.0660

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.0912

GnomAD4 genome AF: 0.0689 AC: 10497 AN: 152292 Hom.: 481 Cov.: 32 AF XY: 0.0650 AC XY: 4837 AN XY: 74468

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0594

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0406

Gnomad4 FIN AF: 0.0707

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0676

Alfa AF: 0.0934 Hom.: 1390

Bravo AF: 0.0655

TwinsUK AF: 0.109 AC: 403

ALSPAC AF: 0.119 AC: 457

ESP6500AA AF: 0.0191 AC: 78

ESP6500EA AF: 0.104 AC: 875

ExAC AF: 0.0518 AC: 6200

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	- -

TNRC6B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.77	T;T;.
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.072
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.074, 0.065
ClinPred		0.023	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9611280; hg19: chr22-40552119; COSMIC: COSV57292828;