Genetic Variant TDRD6:p.Ser3Leu (chr6-46688136-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010870.3(TDRD6):c.8C>T(p.Ser3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,535,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TDRD6
NM_001010870.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05182588).

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.8C>T	p.Ser3Leu	missense	Exon 1 of 4	NP_001010870.1	O60522-1
TDRD6	NM_001168359.2		c.8C>T	p.Ser3Leu	missense	Exon 1 of 3	NP_001161831.1	O60522-2
TDRD6-AS1	NR_134643.1		n.30G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDRD6	ENST00000316081.11	TSL:1 MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 1 of 4	ENSP00000346065.5	O60522-1
TDRD6	ENST00000544460.5	TSL:2	c.8C>T	p.Ser3Leu	missense	Exon 1 of 3	ENSP00000443299.1	O60522-2
TDRD6-AS1	ENST00000434329.3	TSL:3	n.160G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000150

AC:

AN:

133460

AF XY:

0.0000135

show subpopulations

Gnomad AFR exome

AF:

0.000178

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1383336

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30026

American (AMR)

AF:

0.00

AC:

AN:

35360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24680

East Asian (EAS)

AF:

0.00

AC:

AN:

35776

South Asian (SAS)

AF:

0.00

AC:

AN:

79312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079940

Other (OTH)

AF:

0.00

AC:

AN:

57552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000903

AC:

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

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Benign

0.11

Eigen_PC

Benign

0.092

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

2.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.3

REVEL

Benign

0.041

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.17

MutPred

0.32

Loss of glycosylation at S3 (P = 0.0103)

MVP

0.45

MPC

0.041

ClinPred

0.47

GERP RS

3.2

PromoterAI

0.11

Neutral

(source)

Varity_R

0.13

gMVP

0.47

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over