Genetic Variant THUMPD2:p.Asn427Thr (chr2-39736967-T-G) – 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_025264.5(THUMPD2):c.1280A>C(p.Asn427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N427S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THUMPD2
NM_025264.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.653

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: 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=0.05238676).

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.1280A>C	p.Asn427Thr	missense	Exon 10 of 10	NP_079540.2	Q9BTF0-1
THUMPD2	NM_001321469.1		c.1001A>C	p.Asn334Thr	missense	Exon 10 of 10	NP_001308398.1
THUMPD2	NM_001321470.1		c.953A>C	p.Asn318Thr	missense	Exon 10 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.1280A>C	p.Asn427Thr	missense	Exon 10 of 10	ENSP00000423933.1	Q9BTF0-1
THUMPD2	ENST00000378727.8	TSL:1	n.*489A>C		non_coding_transcript_exon	Exon 11 of 11	ENSP00000368001.4	Q9BTF0-2
THUMPD2	ENST00000460072.5	TSL:1	n.2241A>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

0.070

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.7

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.012

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.46

M_CAP

Benign

0.0027

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.40

PhyloP100

0.65

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.29

REVEL

Benign

0.061

Sift

Benign

0.41

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.084

MutPred

0.54

Gain of phosphorylation at N427 (P = 0.023)

MVP

0.030

MPC

0.011

ClinPred

0.024

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.18

Mutation Taster

=91/9

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