NM_001010870.3:c.86C>A

Variant names:

• chr6-46688214-C-A
• rs1438599408
• NM_001010870.3:c.86C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001010870.3(TDRD6):​c.86C>A​(p.Pro29Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000072 in 1,388,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P29L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TDRD6 NM_001010870.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.86C>A	p.Pro29Gln	missense	Exon 1 of 4	NP_001010870.1	O60522-1
	TDRD6	NM_001168359.2		c.86C>A	p.Pro29Gln	missense	Exon 1 of 3	NP_001161831.1	O60522-2
	TDRD6	NR_144468.2		n.1372+6575C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD6	ENST00000316081.11	TSL:1 MANE Select	c.86C>A	p.Pro29Gln	missense	Exon 1 of 4	ENSP00000346065.5	O60522-1
	TDRD6	ENST00000544460.5	TSL:2	c.86C>A	p.Pro29Gln	missense	Exon 1 of 3	ENSP00000443299.1	O60522-2
	TDRD6-AS1	ENST00000434329.3	TSL:3	n.82G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388948 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 686764

⚠️ 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: 30584

American (AMR) AF: 0.00 AC: 0 AN: 35780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24830

East Asian (EAS) AF: 0.00 AC: 0 AN: 36390

South Asian (SAS) AF: 0.00 AC: 0 AN: 79796

European-Finnish (FIN) AF: 0.0000271 AC: 1 AN: 36856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4906

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082020

Other (OTH) AF: 0.00 AC: 0 AN: 57786

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.22
Sift	Benign	0.034	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.60		Gain of catalytic residue at P29 (P = 0.0645)
MVP		0.42
MPC		0.21
ClinPred		0.87	D
GERP RS		5.2
PromoterAI		0.074	Neutral
Varity_R		0.062
gMVP		0.52
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1438599408; hg19: chr6-46655951;