14-103928715-C-T

Variant names:

• chr14-103928715-C-T
• rs992290495
• NM_153046.3:c.206C>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.206C>T​(p.Ala69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,162,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: TDRD9 NM_153046.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.399
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054908305).

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.206C>T	p.Ala69Val	missense	Exon 1 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.206C>T	p.Ala69Val	missense	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.206C>T	p.Ala69Val	missense	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.206C>T	p.Ala69Val	missense	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150794 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

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: 0.0000148

Gnomad OTH AF: 0.000481

GnomAD4 exome AF: 0.00000989 AC: 10 AN: 1011250 Hom.: 0 Cov.: 19 AF XY: 0.00000836 AC XY: 4 AN XY: 478306

African (AFR) AF: 0.00 AC: 0 AN: 20190

American (AMR) AF: 0.00 AC: 0 AN: 6714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11674

East Asian (EAS) AF: 0.00 AC: 0 AN: 21182

South Asian (SAS) AF: 0.00 AC: 0 AN: 19552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2572

European-Non Finnish (NFE) AF: 0.0000104 AC: 9 AN: 864594

Other (OTH) AF: 0.0000257 AC: 1 AN: 38972

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150794 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73598

African (AFR) AF: 0.0000243 AC: 1 AN: 41202

American (AMR) AF: 0.00 AC: 0 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67656

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.93
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.40
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.0040
Sift	Benign	0.34	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.37		Loss of helix (P = 0.0376)
MVP		0.030
MPC		0.21
ClinPred		0.064	T
GERP RS		-3.7
PromoterAI		-0.055	Neutral
Varity_R		0.026
gMVP		0.21
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs992290495; hg19: chr14-104395052;