9-86309223-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_024617.4(TUT7):c.3649A>G(p.Ile1217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUT7 NM_024617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUT7
• BP4: Computational evidence support a benign effect (MetaRNN=0.08841151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUT7	NM_024617.4	c.3649A>G	p.Ile1217Val	missense_variant	21/27	ENST00000375963.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUT7	ENST00000375963.8	c.3649A>G	p.Ile1217Val	missense_variant	21/27	5	NM_024617.4	P1
TUT7	ENST00000375960.6	c.2941A>G	p.Ile981Val	missense_variant	14/20	1
TUT7	ENST00000277141.10	c.1516A>G	p.Ile506Val	missense_variant	22/28	2
TUT7	ENST00000375957.5	c.349A>G	p.Ile117Val	missense_variant	6/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416978 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 706908

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 26, 2023

The c.3649A>G (p.I1217V) alteration is located in exon 21 (coding exon 20) of the ZCCHC6 gene. This alteration results from a A to G substitution at nucleotide position 3649, causing the isoleucine (I) at amino acid position 1217 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Benign	0.94
Eigen	Benign	-0.010
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.79	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.51, 0.11	.;P;.;B
Vest4		0.18
MutPred		0.46		.;.;.;Loss of sheet (P = 0.0104);
MVP		0.18
MPC		0.55
ClinPred		0.40	T
GERP RS		4.4
Varity_R		0.064
gMVP		0.33

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: rs1388022973; hg19: chr9-88924138;