Genetic Variant TDRD6:p.Tyr43Asn (chr6-46688255-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001010870.3(TDRD6):c.127T>A(p.Tyr43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,510,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TDRD6
NM_001010870.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Publications

0 publications found

Variant links:

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 links:

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

TDRD6-AS1 links:

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ACMG classification

Classification was made for transcript

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, 0.84

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDRD6	NM_001010870.3	MANE Select	c.127T>A	p.Tyr43Asn	missense	Exon 1 of 4	NP_001010870.1	O60522-1
TDRD6	NM_001168359.2		c.127T>A	p.Tyr43Asn	missense	Exon 1 of 3	NP_001161831.1	O60522-2
TDRD6	NR_144468.2		n.1372+6616T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDRD6	ENST00000316081.11	TSL:1 MANE Select	c.127T>A	p.Tyr43Asn	missense	Exon 1 of 4	ENSP00000346065.5	O60522-1
TDRD6	ENST00000544460.5	TSL:2	c.127T>A	p.Tyr43Asn	missense	Exon 1 of 3	ENSP00000443299.1	O60522-2
TDRD6-AS1	ENST00000434329.3	TSL:3	n.41A>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000935

AC:

AN:

106928

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000507

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1359464

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

670454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28840

American (AMR)

AF:

0.0000326

AC:

AN:

30646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23552

East Asian (EAS)

AF:

0.00

AC:

AN:

34544

South Asian (SAS)

AF:

0.00

AC:

AN:

76202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4610

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069662

Other (OTH)

AF:

0.00

AC:

AN:

56566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41102

American (AMR)

AF:

0.000131

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67784

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.70

MutPred

0.74

Gain of disorder (P = 0.0207)

MVP

0.49

MPC

0.27

ClinPred

0.99

GERP RS

5.2

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.85

gMVP

0.87

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over