22-40261844-C-T

Position:

• chr22-40261844-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001162501.2(TNRC6B):​c.128C>T​(p.Thr43Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,888 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: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TNRC6B NM_001162501.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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]

LOC124905121 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40657818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.128C>T	p.Thr43Met	missense_variant	4/23	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.128C>T	p.Thr43Met	missense_variant	4/21		NP_055903.2
TNRC6B	NM_001024843.2	c.236C>T	p.Thr79Met	missense_variant	7/24		NP_001020014.1
LOC124905121	XR_007068107.1	n.304-1476G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.128C>T	p.Thr43Met	missense_variant	4/23	2	NM_001162501.2	ENSP00000401946.2
TNRC6B	ENST00000335727.13	c.128C>T	p.Thr43Met	missense_variant	4/21	1		ENSP00000338371.8
TNRC6B	ENST00000402203.5	c.236C>T	p.Thr79Met	missense_variant	7/24	1		ENSP00000384795.1
TNRC6B	ENST00000301923.13	c.236C>T	p.Thr79Met	missense_variant	7/24	5		ENSP00000306759.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417888 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698584

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: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

TNRC6B: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.024	.;.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.95	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.020	D;D;T;T
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.59
MutPred		0.18		.;.;Loss of phosphorylation at T43 (P = 0.0123);Loss of phosphorylation at T43 (P = 0.0123);
MVP		0.19
MPC		0.65
ClinPred		0.82	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.17

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: rs2070389155; hg19: chr22-40657848;