chr22-40156113-A-G

Variant names:

• chr22-40156113-A-G
• rs146996627
• ENST00000402203.5:c.46-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_001024843.2(TNRC6B):​c.46-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000762 in 1,575,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: TNRC6B NM_001024843.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.8619
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 5.72
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000703 (10/1423224) while in subpopulation AMR AF = 0.000233 (9/38544). AF 95% confidence interval is 0.000121. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000464 AC: 9 AN: 193766 AF XY: 0.0000292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.00000703 AC: 10 AN: 1423224 Hom.: 0 Cov.: 30 AF XY: 0.00000284 AC XY: 2 AN XY: 703838

African (AFR) AF: 0.00 AC: 0 AN: 32696

American (AMR) AF: 0.000233 AC: 9 AN: 38544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.00 AC: 0 AN: 38026

South Asian (SAS) AF: 0.00 AC: 0 AN: 80602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091998

Other (OTH) AF: 0.0000169 AC: 1 AN: 59108

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism spectrum disorder Other:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Benign	0.29	N
PhyloP100		5.7
GERP RS		5.5
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Pathogenic	0.79

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

Other links and lift over

dbSNP: rs146996627; hg19: chr22-40552117;