9-86310725-A-G

Variant names:

• chr9-86310725-A-G
• rs753140997
• NM_024617.4:c.3359T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024617.4(TUT7):​c.3359T>C​(p.Ile1120Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TUT7 NM_024617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

TUT7 (HGNC:25817): (terminal uridylyl transferase 7) Enables RNA uridylyltransferase activity and miRNA binding activity. Involved in RNA metabolic process and negative regulation of transposition, RNA-mediated. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUT7	NM_024617.4	c.3359T>C	p.Ile1120Thr	missense_variant	Exon 18 of 27	ENST00000375963.8	NP_078893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUT7	ENST00000375963.8	c.3359T>C	p.Ile1120Thr	missense_variant	Exon 18 of 27	5	NM_024617.4	ENSP00000365130.3
TUT7	ENST00000375960.6	c.2651T>C	p.Ile884Thr	missense_variant	Exon 11 of 20	1		ENSP00000365127.2
TUT7	ENST00000277141.10	c.1226T>C	p.Ile409Thr	missense_variant	Exon 19 of 28	2		ENSP00000277141.6
TUT7	ENST00000375957.5	c.173T>C	p.Ile58Thr	missense_variant	Exon 4 of 12	2		ENSP00000365124.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455082 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724336

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3359T>C (p.I1120T) alteration is located in exon 18 (coding exon 17) of the ZCCHC6 gene. This alteration results from a T to C substitution at nucleotide position 3359, causing the isoleucine (I) at amino acid position 1120 to be replaced by a threonine (T). 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	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.7	.;.;.;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.97
MutPred		0.78		.;.;.;Loss of stability (P = 0.0109);
MVP		0.56
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.96

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: rs753140997; hg19: chr9-88925640;