Genetic Variant TDRD9:p.Gly17Ser (chr14-103928558-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_153046.3(TDRD9):c.49G>A(p.Gly17Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000808 in 1,237,042 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. G17C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

spermatogenic failure 30
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TDRD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4097572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3 link	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 36	ENST00000409874.9	NP_694591.2	Q8NDG6-1Q86WA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD9	ENST00000409874.9 link	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 36	5	NM_153046.3	ENSP00000387303.4		Q8NDG6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.08e-7

AC:

AN:

1237042

Hom.:

Cov.:

AF XY:

0.00000165

AC XY:

AN XY:

606954

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24192

American (AMR)

AF:

0.00

AC:

AN:

17112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19240

East Asian (EAS)

AF:

0.00

AC:

AN:

25736

South Asian (SAS)

AF:

0.00

AC:

AN:

62972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4918

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

989870

Other (OTH)

AF:

0.00

AC:

AN:

48558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

PhyloP100

4.9

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Uncertain

0.021

Sift4G

Uncertain

0.058

Polyphen

1.0

Vest4

0.45

MutPred

0.65

Gain of sheet (P = 0.0149);

MVP

0.51

MPC

0.80

ClinPred

0.93

GERP RS

4.8

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.17

gMVP

0.40

Mutation Taster

=84/16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over