22-40261882-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001162501.2(TNRC6B):c.166A>G(p.Ile56Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000616 in 1,592,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I56T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: TNRC6B NM_001162501.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.90

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]

LOC124905121 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013377339).
• BP6: Variant 22-40261882-A-G is Benign according to our data. Variant chr22-40261882-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2400570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000459 (7/152342) while in subpopulation SAS AF= 0.00124 (6/4828). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNRC6B	NM_001162501.2	c.166A>G	p.Ile56Val	missense_variant	4/23	ENST00000454349.7
LOC124905121	XR_007068107.1	n.304-1514T>C		intron_variant, non_coding_transcript_variant
TNRC6B	NM_015088.3	c.166A>G	p.Ile56Val	missense_variant	4/21
TNRC6B	NM_001024843.2	c.274A>G	p.Ile92Val	missense_variant	7/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNRC6B	ENST00000454349.7	c.166A>G	p.Ile56Val	missense_variant	4/23	2	NM_001162501.2	P3
TNRC6B	ENST00000335727.13	c.166A>G	p.Ile56Val	missense_variant	4/21	1
TNRC6B	ENST00000402203.5	c.274A>G	p.Ile92Val	missense_variant	7/24	1		A2
TNRC6B	ENST00000301923.13	c.274A>G	p.Ile92Val	missense_variant	7/24	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152224 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 30 AN: 244442 Hom.: 0 AF XY: 0.000150 AC XY: 20 AN XY: 133472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000949

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000632 AC: 91 AN: 1439668 Hom.: 0 Cov.: 30 AF XY: 0.0000870 AC XY: 62 AN XY: 712610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000959

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152342 Hom.: 0 Cov.: 31 AF XY: 0.0000671 AC XY: 5 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.16	N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.54	T;T;T;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.0010	B;B;P;B
Vest4		0.40
MutPred		0.054		.;.;Loss of catalytic residue at S58 (P = 0.1639);Loss of catalytic residue at S58 (P = 0.1639);
MVP		0.38
MPC		0.25
ClinPred		0.16	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.044

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

Publications

LitVar

Other links and lift over

dbSNP: rs577487172; hg19: chr22-40657886;