rs12484776

Variant names:

• chr22-40256869-A-G
• rs12484776
• NM_001162501.2:c.116-4963A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001162501.2(TNRC6B):​c.116-4963A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,144 control chromosomes in the GnomAD database, including 3,473 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3473 hom., cov: 32)
• Consequence: TNRC6B NM_001162501.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 30 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.116-4963A>G		intron_variant	Intron 3 of 22	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.116-4963A>G		intron_variant	Intron 3 of 20		NP_055903.2
TNRC6B	NM_001024843.2	c.224-4963A>G		intron_variant	Intron 6 of 23		NP_001020014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.116-4963A>G		intron_variant	Intron 3 of 22	2	NM_001162501.2	ENSP00000401946.2
TNRC6B	ENST00000335727.13	c.116-4963A>G		intron_variant	Intron 3 of 20	1		ENSP00000338371.8
TNRC6B	ENST00000402203.5	c.224-4963A>G		intron_variant	Intron 6 of 23	1		ENSP00000384795.1
TNRC6B	ENST00000301923.13	c.224-4963A>G		intron_variant	Intron 6 of 23	5		ENSP00000306759.9

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29566 AN: 152026 Hom.: 3467 Cov.: 32

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29577 AN: 152144 Hom.: 3473 Cov.: 32 AF XY: 0.201 AC XY: 14942 AN XY: 74400

African (AFR) AF: 0.0995 AC: 4131 AN: 41518

American (AMR) AF: 0.336 AC: 5137 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3472

East Asian (EAS) AF: 0.274 AC: 1416 AN: 5172

South Asian (SAS) AF: 0.303 AC: 1464 AN: 4828

European-Finnish (FIN) AF: 0.234 AC: 2478 AN: 10582

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13600 AN: 67990

Other (OTH) AF: 0.190 AC: 402 AN: 2114

Alfa AF: 0.206 Hom.: 15749

Bravo AF: 0.201

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.71
PhyloP100		-0.026
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12484776; hg19: chr22-40652873;