Genetic Variant THUMPD2:p.Gly384Arg (chr2-39744407-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025264.5(THUMPD2):c.1150G>A(p.Gly384Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THUMPD2
NM_025264.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.26

Publications

0 publications found

Variant links:

Genes affected

THUMPD2 (HGNC:14890): (THUMP domain containing 2) Predicted to enable tRNA (guanine) methyltransferase activity. Predicted to be involved in tRNA methylation. [provided by Alliance of Genome Resources, Apr 2022]

THUMPD2 links:

LOC124905994 (HGNC:):

LOC124905994 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10485831).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THUMPD2	NM_025264.5	MANE Select	c.1150G>A	p.Gly384Arg	missense	Exon 9 of 10	NP_079540.2	Q9BTF0-1
THUMPD2	NM_001321469.1		c.871G>A	p.Gly291Arg	missense	Exon 9 of 10	NP_001308398.1
THUMPD2	NM_001321470.1		c.823G>A	p.Gly275Arg	missense	Exon 9 of 10	NP_001308399.1	B4DP37

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THUMPD2	ENST00000505747.6	TSL:1 MANE Select	c.1150G>A	p.Gly384Arg	missense	Exon 9 of 10	ENSP00000423933.1	Q9BTF0-1
THUMPD2	ENST00000378727.8	TSL:1	n.*359G>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000368001.4	Q9BTF0-2
THUMPD2	ENST00000460072.5	TSL:1	n.2111G>A		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1430678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711380

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:

31442

American (AMR)

AF:

0.00

AC:

AN:

38246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37480

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100402

Other (OTH)

AF:

0.00

AC:

AN:

59074

⚠️ 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: 0.250

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

Benign

0.18

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.013

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.71

M_CAP

Benign

0.0066

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

PhyloP100

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.4

REVEL

Benign

0.047

Sift

Benign

0.17

Sift4G

Benign

0.23

Polyphen

0.012

Vest4

0.25

MutPred

0.55

Gain of MoRF binding (P = 0.0162)

MVP

0.30

MPC

0.016

ClinPred

0.33

GERP RS

3.8

Varity_R

0.043

gMVP

0.46

Mutation Taster

=83/17

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