chr22-40261969-C-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001162501.2(TNRC6B):āc.253C>Gā(p.Arg85Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
TNRC6B
NM_001162501.2 missense
NM_001162501.2 missense
Scores
8
3
6
Clinical Significance
Conservation
PhyloP100: 7.57
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNRC6B | NM_001162501.2 | c.253C>G | p.Arg85Gly | missense_variant | 4/23 | ENST00000454349.7 | |
LOC124905121 | XR_007068107.1 | n.304-1601G>C | intron_variant, non_coding_transcript_variant | ||||
TNRC6B | NM_015088.3 | c.253C>G | p.Arg85Gly | missense_variant | 4/21 | ||
TNRC6B | NM_001024843.2 | c.361C>G | p.Arg121Gly | missense_variant | 7/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNRC6B | ENST00000454349.7 | c.253C>G | p.Arg85Gly | missense_variant | 4/23 | 2 | NM_001162501.2 | P3 | |
TNRC6B | ENST00000335727.13 | c.253C>G | p.Arg85Gly | missense_variant | 4/21 | 1 | |||
TNRC6B | ENST00000402203.5 | c.361C>G | p.Arg121Gly | missense_variant | 7/24 | 1 | A2 | ||
TNRC6B | ENST00000301923.13 | c.361C>G | p.Arg121Gly | missense_variant | 7/24 | 5 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460366Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726448
GnomAD4 exome
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1
AN:
1460366
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30
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0
AN XY:
726448
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Global developmental delay with speech and behavioral abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with global developmental delay with speech and behavioural abnormalities (MIM#619243). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, an alternative change (p.(Arg85His)) has been reported in an ExAC derived control cohort (PMID: 33004838). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0904 - Non-segregation of this variant with the phenotype under investigation has been clearly demonstrated. It is inherited from an unaffected parent. (SB) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D
Sift4G
Benign
T;T;D;D
Polyphen
D;D;D;D
Vest4
MutPred
0.22
.;.;Loss of methylation at R85 (P = 0.0098);Loss of methylation at R85 (P = 0.0098);
MVP
MPC
0.72
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.