22-40261867-A-G

Position:

• chr22-40261867-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.151A>G​(p.Thr51Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,582,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TNRC6B NM_001162501.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.409

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=0.038804054).
• BP6: Variant 22-40261867-A-G is Benign according to our data. Variant chr22-40261867-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3327739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000263 (4/152248) while in subpopulation SAS AF= 0.000622 (3/4824). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.151A>G	p.Thr51Ala	missense_variant	4/23	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.151A>G	p.Thr51Ala	missense_variant	4/21		NP_055903.2
TNRC6B	NM_001024843.2	c.259A>G	p.Thr87Ala	missense_variant	7/24		NP_001020014.1
LOC124905121	XR_007068107.1	n.304-1499T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.151A>G	p.Thr51Ala	missense_variant	4/23	2	NM_001162501.2	ENSP00000401946.2
TNRC6B	ENST00000335727.13	c.151A>G	p.Thr51Ala	missense_variant	4/21	1		ENSP00000338371.8
TNRC6B	ENST00000402203.5	c.259A>G	p.Thr87Ala	missense_variant	7/24	1		ENSP00000384795.1
TNRC6B	ENST00000301923.13	c.259A>G	p.Thr87Ala	missense_variant	7/24	5		ENSP00000306759.9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152130 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: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000410 AC: 10 AN: 243898 Hom.: 0 AF XY: 0.0000375 AC XY: 5 AN XY: 133204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 30 AN: 1430500 Hom.: 0 Cov.: 30 AF XY: 0.0000255 AC XY: 18 AN XY: 706450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000644

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000663 AC: 8

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

Mar 30, 2024

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	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.015	.;.;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T;.;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.30
MutPred		0.11		.;.;Loss of glycosylation at T51 (P = 0.0079);Loss of glycosylation at T51 (P = 0.0079);
MVP		0.27
MPC		0.14
ClinPred		0.027	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.064

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: rs558788424; hg19: chr22-40657871;