6-46688214-C-T

Position:

• chr6-46688214-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010870.3(TDRD6):​c.86C>T​(p.Pro29Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000216 in 1,388,946 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: 0.0000022 (0 hom.)
• Consequence: TDRD6 NM_001010870.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35968664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDRD6	NM_001010870.3	c.86C>T	p.Pro29Leu	missense_variant	1/4	ENST00000316081.11	NP_001010870.1
TDRD6	NM_001168359.2	c.86C>T	p.Pro29Leu	missense_variant	1/3		NP_001161831.1
TDRD6	NR_144468.2	n.1372+6575C>T		intron_variant
TDRD6-AS1	NR_134643.1	n.-49G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDRD6	ENST00000316081.11	c.86C>T	p.Pro29Leu	missense_variant	1/4	1	NM_001010870.3	ENSP00000346065.5
TDRD6	ENST00000544460.5	c.86C>T	p.Pro29Leu	missense_variant	1/3	2		ENSP00000443299.1
TDRD6-AS1	ENST00000434329.2	n.-49G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1388946 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 686762

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: 0.00000185

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jul 21, 2021

The c.86C>T (p.P29L) alteration is located in exon 1 (coding exon 1) of the TDRD6 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the proline (P) at amino acid position 29 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	Benign	0.26
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.034	.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.26	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.25	.;B
Vest4		0.64
MutPred		0.60		Gain of catalytic residue at P29 (P = 0.1949);Gain of catalytic residue at P29 (P = 0.1949);
MVP		0.32
MPC		0.031
ClinPred		0.30	T
GERP RS		5.2
Varity_R		0.047
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1438599408; hg19: chr6-46655951; COSMIC: COSV100288541; COSMIC: COSV100288541;