Genetic Variant NM_001366102.1:c.287A>G (chr19-32738959-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001366102.1(TDRD12):c.287A>G(p.Asp96Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,556 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. D96A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TDRD12
NM_001366102.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.04

Publications

0 publications found

Variant links:

Genes affected

TDRD12 (HGNC:25044): (tudor domain containing 12) Predicted to enable ATP binding activity; RNA helicase activity; and nucleic acid binding activity. Predicted to be involved in several processes, including gamete generation; gene silencing by RNA; and piRNA metabolic process. Predicted to be part of PET complex. [provided by Alliance of Genome Resources, Apr 2022]

TDRD12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366102.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDRD12	NM_001366102.1	MANE Select	c.287A>G	p.Asp96Gly	missense	Exon 3 of 33	NP_001353031.1	A0A1W2PRK2
TDRD12	NM_001437947.1		c.287A>G	p.Asp96Gly	missense	Exon 3 of 33	NP_001424876.1	A0A2R8Y872
TDRD12	NM_001438799.1		c.287A>G	p.Asp96Gly	missense	Exon 3 of 33	NP_001425728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDRD12	ENST00000639142.2	TSL:5 MANE Select	c.287A>G	p.Asp96Gly	missense	Exon 3 of 33	ENSP00000492643.2	A0A1W2PRK2
TDRD12	ENST00000444215.6	TSL:1	c.287A>G	p.Asp96Gly	missense	Exon 3 of 28	ENSP00000416248.2	Q587J7-1
TDRD12	ENST00000647536.1		c.287A>G	p.Asp96Gly	missense	Exon 3 of 33	ENSP00000496698.1	A0A2R8Y872

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398556

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689798

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31578

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4994

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078956

Other (OTH)

AF:

0.0000173

AC:

AN:

57940

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.45

PhyloP100

6.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.72

Loss of sheet (P = 1e-04)

MVP

0.45

ClinPred

1.0

GERP RS

5.6

Varity_R

0.81

Mutation Taster

=77/23

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over