Genetic Variant ENST00000402203.5:c.46-2A>T (chr22-40156113-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The ENST00000402203.5(TNRC6B):c.46-2A>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000703 in 1,423,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TNRC6B
ENST00000402203.5 splice_acceptor, intron

Scores

Splicing: ADA: 0.8599

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.72

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: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022006473 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of 9, new splice context is: tgcctttgctggtggaacAGgag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001024843.2 link	c.46-2A>T		splice_acceptor_variant, intron_variant	Intron 3 of 23		NP_001020014.1	Q9UPQ9-2A0A024R1N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000402203.5 link	c.46-2A>T		splice_acceptor_variant, intron_variant	Intron 3 of 23	1		ENSP00000384795.1		Q9UPQ9-2
TNRC6B	ENST00000301923.13 link	c.46-2A>T		splice_acceptor_variant, intron_variant	Intron 3 of 23	5		ENSP00000306759.9		Q9UPQ9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1423224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32696

American (AMR)

AF:

0.00

AC:

AN:

38544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25388

East Asian (EAS)

AF:

0.00

AC:

AN:

38026

South Asian (SAS)

AF:

0.00

AC:

AN:

80602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091998

Other (OTH)

AF:

0.00

AC:

AN:

59108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Benign

0.29

PhyloP100

5.7

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.86

dbscSNV1_RF

Pathogenic

0.83

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

Publications

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ENST00000402203.5:c.46-2A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over