chr22-40251194-A-G

Position:

• chr22-40251194-A-G

Variant summary

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

The NM_001162501.2(TNRC6B):​c.109A>G​(p.Thr37Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TNRC6B NM_001162501.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

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 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=0.28487664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.109A>G	p.Thr37Ala	missense_variant	3/23	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.109A>G	p.Thr37Ala	missense_variant	3/21		NP_055903.2
TNRC6B	NM_001024843.2	c.217A>G	p.Thr73Ala	missense_variant	6/24		NP_001020014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.109A>G	p.Thr37Ala	missense_variant	3/23	2	NM_001162501.2	ENSP00000401946.2
TNRC6B	ENST00000335727.13	c.109A>G	p.Thr37Ala	missense_variant	3/21	1		ENSP00000338371.8
TNRC6B	ENST00000402203.5	c.217A>G	p.Thr73Ala	missense_variant	6/24	1		ENSP00000384795.1
TNRC6B	ENST00000301923.13	c.217A>G	p.Thr73Ala	missense_variant	6/24	5		ENSP00000306759.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

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

GeneDx

May 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;.;L;L
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.97	D;D;P;D
Vest4		0.48
MutPred		0.12		.;.;Loss of phosphorylation at T37 (P = 0.0131);Loss of phosphorylation at T37 (P = 0.0131);
MVP		0.54
MPC		0.14
ClinPred		0.64	D
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.082
gMVP		0.077

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: rs2070187273; hg19: chr22-40647198;