14-103955743-C-T

Variant names:

• chr14-103955743-C-T
• rs77852716
• NM_153046.3:c.295C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153046.3(TDRD9):​c.295C>T​(p.Arg99Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,551,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TDRD9 NM_153046.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.573
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023461461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3	c.295C>T	p.Arg99Cys	missense_variant	Exon 2 of 36	ENST00000409874.9	NP_694591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD9	ENST00000409874.9	c.295C>T	p.Arg99Cys	missense_variant	Exon 2 of 36	5	NM_153046.3	ENSP00000387303.4
TDRD9	ENST00000496087.5	n.307C>T		non_coding_transcript_exon_variant	Exon 3 of 5	4
TDRD9	ENST00000554571.1	n.170C>T		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151992 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156724 AF XY: 0.00

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000107 AC: 15 AN: 1399104 Hom.: 0 Cov.: 30 AF XY: 0.00000869 AC XY: 6 AN XY: 690066

African (AFR) AF: 0.000127 AC: 4 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35724

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078814

Other (OTH) AF: 0.0000345 AC: 2 AN: 57990

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152110 Hom.: 0 Cov.: 30 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

African (AFR) AF: 0.0000964 AC: 4 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000794 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295C>T (p.R99C) alteration is located in exon 2 (coding exon 2) of the TDRD9 gene. This alteration results from a C to T substitution at nucleotide position 295, causing the arginine (R) at amino acid position 99 to be replaced by a cysteine (C). 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	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.53
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.57
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.026
Sift	Benign	0.18	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0	B
Vest4		0.072
MVP		0.11
MPC		0.29
ClinPred		0.011	T
GERP RS		-0.23
Varity_R		0.063
gMVP		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77852716; hg19: chr14-104422080;