Variant 1-151778903-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001083965.2(TDRKH):c.665G>A(p.Arg222Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TDRKH
NM_001083965.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

Variant links:

Genes affected

TDRKH (HGNC:11713): (tudor and KH domain containing) Predicted to enable RNA binding activity. Predicted to be involved in fertilization; gamete generation; and piRNA metabolic process. Predicted to be located in mitochondrion; pi-body; and piP-body. [provided by Alliance of Genome Resources, Apr 2022]

TDRKH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08132604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDRKH	NM_001083965.2 linkuse as main transcript	c.665G>A	p.Arg222Lys	missense_variant	6/13	ENST00000368824.8	NP_001077434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDRKH	ENST00000368824.8 linkuse as main transcript	c.665G>A	p.Arg222Lys	missense_variant	6/13	1	NM_001083965.2	ENSP00000357815	P1	Q9Y2W6-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249494

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2022

The c.665G>A (p.R222K) alteration is located in exon 6 (coding exon 5) of the TDRKH gene. This alteration results from a G to A substitution at nucleotide position 665, causing the arginine (R) at amino acid position 222 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0094

T;.;.;T;.;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.66

.;T;T;.;T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.081

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;.;L;.;L;L

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.53

N;.;N;N;N;N;N

REVEL

Benign

0.092

Sift

Benign

0.51

T;.;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Polyphen

0.82

P;.;.;P;P;P;P

Vest4

0.35

MutPred

0.32

Gain of ubiquitination at R222 (P = 0.0022);Gain of ubiquitination at R222 (P = 0.0022);.;Gain of ubiquitination at R222 (P = 0.0022);.;Gain of ubiquitination at R222 (P = 0.0022);Gain of ubiquitination at R222 (P = 0.0022);

MVP

0.60

MPC

0.56

ClinPred

0.12

GERP RS

4.4

Varity_R

0.056

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over