chr14-103928653-C-A

Variant names:

• chr14-103928653-C-A
• rs867213957
• NM_153046.3:c.144C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_153046.3(TDRD9):​c.144C>A​(p.Pro48Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000091 in 1,098,368 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. Synonymous variant affecting the same amino acid position (i.e. P48P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: TDRD9 NM_153046.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.

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.144C>A	p.Pro48Pro	synonymous	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.144C>A	p.Pro48Pro	synonymous	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.144C>A	p.Pro48Pro	synonymous	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.144C>A	p.Pro48Pro	synonymous	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.10e-7 AC: 1 AN: 1098368 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 524396

⚠️ 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: 21758

American (AMR) AF: 0.00 AC: 0 AN: 8062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13434

East Asian (EAS) AF: 0.00 AC: 0 AN: 23930

South Asian (SAS) AF: 0.0000313 AC: 1 AN: 31908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 917690

Other (OTH) AF: 0.00 AC: 0 AN: 42502

⚠️ 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
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.91
DANN	Benign	0.84
PhyloP100		-0.79
PromoterAI		-0.017	Neutral

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: rs867213957; hg19: chr14-104394990;