rs77260485

Variant names:

• chr14-103963088-C-T
• rs77260485
• NM_153046.3:c.332C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: TDRD9 NM_153046.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.646
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 718196.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153046.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD9	NM_153046.3	MANE Select	c.332C>T	p.Pro111Leu	missense	Exon 3 of 36	NP_694591.2	Q8NDG6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD9	ENST00000409874.9	TSL:5 MANE Select	c.332C>T	p.Pro111Leu	missense	Exon 3 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.332C>T	p.Pro111Leu	missense	Exon 3 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.332C>T	p.Pro111Leu	missense	Exon 3 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 151834 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.000537 AC: 80 AN: 149038 AF XY: 0.000329

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 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.: 2 Cov.: 28 AF XY: 0.000169 AC XY: 116 AN XY: 686068

African (AFR) AF: 0.00910 AC: 284 AN: 31208

American (AMR) AF: 0.000207 AC: 7 AN: 33738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35522

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075846

Other (OTH) AF: 0.000364 AC: 21 AN: 57682

GnomAD4 genome AF: 0.00235 AC: 357 AN: 151952 Hom.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 169 AN XY: 74256

African (AFR) AF: 0.00830 AC: 344 AN: 41426

American (AMR) AF: 0.000722 AC: 11 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00271

ESP6500AA AF: 0.00939 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000851 AC: 21

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	TDRD9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.65
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.056
Sift	Benign	0.17	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.13
MPC		0.21
ClinPred		0.0056	T
GERP RS		2.4
Varity_R		0.041
gMVP		0.33
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs77260485; hg19: chr14-104429425;