22-40261943-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001162501.2(TNRC6B):c.227C>T(p.Pro76Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNRC6B
NM_001162501.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.85

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 links:

LOC124905121 (HGNC:):

LOC124905121 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21887806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TNRC6B	NM_001162501.2 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/23	ENST00000454349.7
LOC124905121	XR_007068107.1 linkuse as main transcript	n.304-1575G>A		intron_variant, non_coding_transcript_variant
TNRC6B	NM_015088.3 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/21
TNRC6B	NM_001024843.2 linkuse as main transcript	c.335C>T	p.Pro112Leu	missense_variant	7/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNRC6B	ENST00000454349.7 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/23	2	NM_001162501.2	P3	Q9UPQ9-3
TNRC6B	ENST00000335727.13 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/21	1			Q9UPQ9-1
TNRC6B	ENST00000402203.5 linkuse as main transcript	c.335C>T	p.Pro112Leu	missense_variant	7/24	1		A2	Q9UPQ9-2
TNRC6B	ENST00000301923.13 linkuse as main transcript	c.335C>T	p.Pro112Leu	missense_variant	7/24	5		A2	Q9UPQ9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246306

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726450

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TNRC6B-related conditions. This variant is present in population databases (rs770438837, ExAC 0.002%). This sequence change replaces proline with leucine at codon 76 of the TNRC6B protein (p.Pro76Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Benign

0.0093

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-1.2

MutationTaster

Benign

0.88

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.098

T;T;D;D

Sift4G

Uncertain

0.015

D;D;T;T

Polyphen

0.94

P;P;P;P

Vest4

0.63

MutPred

0.28

.;.;Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.12

MPC

0.64

ClinPred

0.74

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.081

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over