6-46688255-T-C

Variant names:

• chr6-46688255-T-C
• rs1327334117
• NM_001010870.3:c.127T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001010870.3(TDRD6):​c.127T>C​(p.Tyr43His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,359,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y43N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TDRD6 NM_001010870.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010870.3. 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
	TDRD6	NM_001010870.3	MANE Select	c.127T>C	p.Tyr43His	missense	Exon 1 of 4	NP_001010870.1	O60522-1
	TDRD6	NM_001168359.2		c.127T>C	p.Tyr43His	missense	Exon 1 of 3	NP_001161831.1	O60522-2
	TDRD6	NR_144468.2		n.1372+6616T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD6	ENST00000316081.11	TSL:1 MANE Select	c.127T>C	p.Tyr43His	missense	Exon 1 of 4	ENSP00000346065.5	O60522-1
	TDRD6	ENST00000544460.5	TSL:2	c.127T>C	p.Tyr43His	missense	Exon 1 of 3	ENSP00000443299.1	O60522-2
	TDRD6-AS1	ENST00000434329.3	TSL:3	n.41A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1359464 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 670454

African (AFR) AF: 0.00 AC: 0 AN: 28840

American (AMR) AF: 0.00 AC: 0 AN: 30646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23552

East Asian (EAS) AF: 0.00 AC: 0 AN: 34544

South Asian (SAS) AF: 0.00 AC: 0 AN: 76202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069662

Other (OTH) AF: 0.0000177 AC: 1 AN: 56566

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.76		Gain of disorder (P = 0.0212)
MVP		0.44
MPC		0.25
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.083	Neutral
Varity_R		0.69
gMVP		0.78
Mutation Taster		=78/22	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: rs1327334117; hg19: chr6-46655992;