Genetic Variant TNRC6B:p.Gln6* (chr22-40246025-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001162501.2(TNRC6B):c.16C>T(p.Gln6*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000727 in 1,375,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TNRC6B
NM_001162501.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.00

Publications

0 publications found

Variant links:

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]

TNRC6B Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
global developmental delay with speech and behavioral abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNRC6B links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 51 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-40246025-C-T is Pathogenic according to our data. Variant chr22-40246025-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1527918.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001162501.2 link	c.16C>T	p.Gln6*	stop_gained	Exon 2 of 23	ENST00000454349.7	NP_001155973.1	Q9UPQ9-3
TNRC6B	NM_015088.3 link	c.16C>T	p.Gln6*	stop_gained	Exon 2 of 21		NP_055903.2	Q9UPQ9-1
TNRC6B	NM_001024843.2 link	c.124C>T	p.Gln42*	stop_gained	Exon 5 of 24		NP_001020014.1	Q9UPQ9-2A0A024R1N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7 link	c.16C>T	p.Gln6*	stop_gained	Exon 2 of 23	2	NM_001162501.2	ENSP00000401946.2		Q9UPQ9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1375240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

677976

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30478

American (AMR)

AF:

0.00

AC:

AN:

33974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24318

East Asian (EAS)

AF:

0.0000290

AC:

AN:

34516

South Asian (SAS)

AF:

0.00

AC:

AN:

77786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065844

Other (OTH)

AF:

0.00

AC:

AN:

56498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Global developmental delay with speech and behavioral abnormalities

Pathogenic:1

Apr 04, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.70

PhyloP100

5.0

Vest4

0.38

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=19/181

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over