11-62575383-C-T

Variant names:

• chr11-62575383-C-T
• rs200914716
• NM_022830.3:c.2336G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_022830.3(TUT1):​c.2336G>A​(p.Arg779Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TUT1 NM_022830.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

Genes affected

TUT1 (HGNC:26184): (terminal uridylyl transferase 1, U6 snRNA-specific) This gene encodes a nucleotidyl transferase that functions as both a terminal uridylyltransferase and a nuclear poly(A) polymerase. The encoded enzyme specifically adds and removes nucleotides from the 3' end of small nuclear RNAs and select mRNAs and may function in controlling gene expression and cell proliferation.[provided by RefSeq, Apr 2009]

ENSG00000255508 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Reduced terminal uridylyltransferase activity; when associated with A-783. (size 0) in uniprot entity STPAP_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUT1	NM_022830.3	c.2336G>A	p.Arg779Gln	missense_variant	Exon 9 of 9	ENST00000476907.6	NP_073741.3
TUT1	NM_001367906.1	c.*750G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001354835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUT1	ENST00000476907.6	c.2336G>A	p.Arg779Gln	missense_variant	Exon 9 of 9	1	NM_022830.3	ENSP00000419607.1
ENSG00000255508	ENST00000496634.2	n.1475-475G>A		intron_variant	Intron 8 of 16	2		ENSP00000456163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460462 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726620

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000628 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2450G>A (p.R817Q) alteration is located in exon 9 (coding exon 9) of the TUT1 gene. This alteration results from a G to A substitution at nucleotide position 2450, causing the arginine (R) at amino acid position 817 to be replaced by a glutamine (Q). 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.43
MVP		0.81
MPC		0.88
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.72

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: rs200914716; hg19: chr11-62342855;