Genetic Variant TDRD9:p.Pro111Leu (chr14-103963088-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_153046.3(TDRD9):c.332C>T(p.Pro111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,543,076 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.646

Variant links:

Genes affected

TDRD9 (HGNC:20122): (tudor domain containing 9) Predicted to enable RNA binding activity. Involved in spermatogenesis. Located in cytoplasm and nucleus. Implicated in spermatogenic failure 30. [provided by Alliance of Genome Resources, Apr 2022]

TDRD9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033640862).

BP6

Variant 14-103963088-C-T is Benign according to our data. Variant chr14-103963088-C-T is described in ClinVar as [Benign]. Clinvar id is 718196.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00235 (357/151952) while in subpopulation AFR AF= 0.0083 (344/41426). AF 95% confidence interval is 0.00758. There are 2 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3 link	c.332C>T	p.Pro111Leu	missense_variant	Exon 3 of 36	ENST00000409874.9	NP_694591.2	Q8NDG6-1Q86WA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TDRD9	ENST00000409874.9 link	c.332C>T	p.Pro111Leu	missense_variant	Exon 3 of 36	5	NM_153046.3	ENSP00000387303.4	Q8NDG6-1
TDRD9	ENST00000496087.5 link	n.344C>T		non_coding_transcript_exon_variant	Exon 4 of 5	4
TDRD9	ENST00000554571.1 link	n.207C>T		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00833

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

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:

0.000480

GnomAD3 exomes

AF:

0.000537

AC:

AN:

149038

Hom.:

AF XY:

0.000329

AC XY:

AN XY:

79040

show subpopulations

Gnomad AFR exome

AF:

0.00931

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000479

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.000226

AC:

315

AN:

1391124

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

116

AN XY:

686068

show subpopulations

Gnomad4 AFR exome

AF:

0.00910

Gnomad4 AMR exome

AF:

0.000207

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000258

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.30e-7

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.00235

AC:

357

AN:

151952

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

169

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00830

Gnomad4 AMR

AF:

0.000722

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00271

ESP6500AA

AF:

0.00939

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000851

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TDRD9-related disorder

Benign:1

Aug 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.038

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.46

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

REVEL

Benign

0.056

Sift

Benign

0.17

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.059

MVP

0.13

MPC

0.21

ClinPred

0.0056

GERP RS

2.4

Varity_R

0.041

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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