NM_153046.3:c.49G>A

Variant names:

• chr14-103928558-G-A
• rs1294873202
• NM_153046.3:c.49G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• 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: 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).

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.49G>A	p.Gly17Ser	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.49G>A	p.Gly17Ser	missense	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.49G>A	p.Gly17Ser	missense	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.49G>A	p.Gly17Ser	missense	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.08e-7 AC: 1 AN: 1237042 Hom.: 0 Cov.: 33 AF XY: 0.00000165 AC XY: 1 AN XY: 606954

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

African (AFR) AF: 0.00 AC: 0 AN: 24192

American (AMR) AF: 0.00 AC: 0 AN: 17112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19240

East Asian (EAS) AF: 0.00 AC: 0 AN: 25736

South Asian (SAS) AF: 0.00 AC: 0 AN: 62972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4918

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 989870

Other (OTH) AF: 0.00 AC: 0 AN: 48558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.65		Gain of sheet (P = 0.0149)
MVP		0.51
MPC		0.80
ClinPred		0.93	D
GERP RS		4.8
PromoterAI		-0.15	Neutral
Varity_R		0.17
gMVP		0.40
Mutation Taster		=84/16	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: rs1294873202; hg19: chr14-104394895;