2-39761336-T-G

Position:

• chr2-39761336-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025264.5(THUMPD2):​c.886A>C​(p.Ile296Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: THUMPD2 NM_025264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36854315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THUMPD2	NM_025264.5	c.886A>C	p.Ile296Leu	missense_variant	6/10	ENST00000505747.6	NP_079540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THUMPD2	ENST00000505747.6	c.886A>C	p.Ile296Leu	missense_variant	6/10	1	NM_025264.5	ENSP00000423933.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461446 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.886A>C (p.I296L) alteration is located in exon 6 (coding exon 6) of the THUMPD2 gene. This alteration results from a A to C substitution at nucleotide position 886, causing the isoleucine (I) at amino acid position 296 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.18
Sift	Benign	0.38	T
Sift4G	Benign	0.26	T
Polyphen		0.33	B
Vest4		0.57
MutPred		0.54		Gain of ubiquitination at K297 (P = 0.1295);
MVP		0.12
MPC		0.049
ClinPred		0.76	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs776225848; hg19: chr2-39988476;