Genetic Variant NM_001162501.2:c.157G>T (chr22-40261873-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001162501.2(TNRC6B):c.157G>T(p.Ala53Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000296 in 1,585,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

TNRC6B
NM_001162501.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.53

Publications

5 publications found

Variant links:

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

TNRC6B links:

ENSG00000309895 (HGNC:):

ENSG00000309895 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19549188).

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001162501.2 link	c.157G>T	p.Ala53Ser	missense_variant	Exon 4 of 23	ENST00000454349.7	NP_001155973.1	Q9UPQ9-3
TNRC6B	NM_015088.3 link	c.157G>T	p.Ala53Ser	missense_variant	Exon 4 of 21		NP_055903.2	Q9UPQ9-1
TNRC6B	NM_001024843.2 link	c.265G>T	p.Ala89Ser	missense_variant	Exon 7 of 24		NP_001020014.1	Q9UPQ9-2A0A024R1N5
LOC124905121	XR_007068107.1 link	n.304-1505C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7 link	c.157G>T	p.Ala53Ser	missense_variant	Exon 4 of 23	2	NM_001162501.2	ENSP00000401946.2		Q9UPQ9-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

244068

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1433094

Hom.:

Cov.:

AF XY:

0.0000311

AC XY:

AN XY:

708380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33106

American (AMR)

AF:

0.00

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25766

East Asian (EAS)

AF:

0.0000769

AC:

AN:

39000

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000358

AC:

AN:

1088848

Other (OTH)

AF:

0.0000510

AC:

AN:

58782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

.;.;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;.;D;D

M_CAP

Benign

0.0058

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

.;.;M;M

PhyloP100

6.5

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.64

T;T;T;T

Polyphen

0.88

P;P;P;P

Vest4

0.43

MutPred

0.12

.;.;Gain of phosphorylation at A53 (P = 0.0058);Gain of phosphorylation at A53 (P = 0.0058);

MVP

0.31

MPC

0.61

ClinPred

0.28

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.14

Mutation Taster

=76/24

polymorphism

(source)

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

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NM_001162501.2:c.157G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over