6-46688188-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010870.3(TDRD6):c.60C>G(p.Phe20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,397,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TDRD6 NM_001010870.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0910

Genes affected

TDRD6 (HGNC:21339): (tudor domain containing 6) This gene encodes a tudor domain-containing protein and component of the chromatoid body, a type of ribonucleoprotein granule present in male germ cells. Studies in rodents have demonstrated a role for the encoded protein in spermiogenesis and the nonsense mediated decay (NMD) pathway. This protein is a major autoantigen in human patients with autoimmune polyendocrine syndrome type 1 (APS1). [provided by RefSeq, Oct 2016]

TDRD6-AS1 (HGNC:56119): (TDRD6 and SLC25A27 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20586595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD6	NM_001010870.3	c.60C>G	p.Phe20Leu	missense_variant	1/4	ENST00000316081.11
TDRD6	NM_001168359.2	c.60C>G	p.Phe20Leu	missense_variant	1/3
TDRD6	NR_144468.2	n.1372+6549C>G		intron_variant, non_coding_transcript_variant
TDRD6-AS1	NR_134643.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD6	ENST00000316081.11	c.60C>G	p.Phe20Leu	missense_variant	1/4	1	NM_001010870.3	P2
TDRD6	ENST00000544460.5	c.60C>G	p.Phe20Leu	missense_variant	1/3	2		A2
TDRD6-AS1	ENST00000434329.2			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1397628 Hom.: 0 Cov.: 29 AF XY: 0.0000130 AC XY: 9 AN XY: 691558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2023

The c.60C>G (p.F20L) alteration is located in exon 1 (coding exon 1) of the TDRD6 gene. This alteration results from a C to G substitution at nucleotide position 60, causing the phenylalanine (F) at amino acid position 20 to be replaced by a leucine (L). 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.74	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.17
Sift	Benign	0.29	T;T
Sift4G	Benign	0.084	T;T
Polyphen		0.98	.;D
Vest4		0.37
MutPred		0.69		Loss of catalytic residue at F20 (P = 0.0419);Loss of catalytic residue at F20 (P = 0.0419);
MVP		0.25
MPC		0.044
ClinPred		0.40	T
GERP RS		2.3
Varity_R		0.084
gMVP		0.45

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46655925;