6-46688322-C-T

Variant summary

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

The NM_001010870.3(TDRD6):c.194C>T(p.Ala65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: TDRD6 NM_001010870.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282

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]

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=0.12467089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD6	NM_001010870.3	c.194C>T	p.Ala65Val	missense_variant	1/4	ENST00000316081.11
TDRD6	NM_001168359.2	c.194C>T	p.Ala65Val	missense_variant	1/3
TDRD6	NR_144468.2	n.1372+6683C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD6	ENST00000316081.11	c.194C>T	p.Ala65Val	missense_variant	1/4	1	NM_001010870.3	P2
TDRD6	ENST00000544460.5	c.194C>T	p.Ala65Val	missense_variant	1/3	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Jul 19, 2022

The c.194C>T (p.A65V) 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 194, causing the alanine (A) at amino acid position 65 to be replaced by a valine (V). 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	0.098
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.12
Sift	Benign	0.25	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.27	.;B
Vest4		0.17
MutPred		0.44		Loss of disorder (P = 0.0752);Loss of disorder (P = 0.0752);
MVP		0.26
MPC		0.037
ClinPred		0.22	T
GERP RS		5.2
Varity_R		0.084
gMVP		0.20

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: chr6-46656059;