22-40316633-G-A

Variant names:

• chr22-40316633-G-A
• rs6001877
• NM_001162501.2:c.4974+621G>A

Variant summary

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

The NM_001162501.2(TNRC6B):​c.4974+621G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,976 control chromosomes in the GnomAD database, including 7,622 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 0.30 (7622 hom., cov: 31)
• Consequence: TNRC6B NM_001162501.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.4974+621G>A		intron_variant	Intron 21 of 22	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.4644+621G>A		intron_variant	Intron 19 of 20		NP_055903.2
TNRC6B	NM_001024843.2	c.2562+621G>A		intron_variant	Intron 22 of 23		NP_001020014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.4974+621G>A		intron_variant	Intron 21 of 22	2	NM_001162501.2	ENSP00000401946.2

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44907 AN: 151858 Hom.: 7607 Cov.: 31

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.296 AC: 44953 AN: 151976 Hom.: 7622 Cov.: 31 AF XY: 0.304 AC XY: 22571 AN XY: 74276

African (AFR) AF: 0.141 AC: 5828 AN: 41462

American (AMR) AF: 0.408 AC: 6232 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2210 AN: 5148

South Asian (SAS) AF: 0.450 AC: 2170 AN: 4818

European-Finnish (FIN) AF: 0.370 AC: 3911 AN: 10558

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22545 AN: 67936

Other (OTH) AF: 0.293 AC: 619 AN: 2112

Alfa AF: 0.331 Hom.: 4677

Bravo AF: 0.294

Asia WGS AF: 0.476 AC: 1655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.88
DANN	Benign	0.31
PhyloP100		-0.54
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: rs6001877; hg19: chr22-40712637;