21-37090249-T-C

Position:

• chr21-37090249-T-C

Variant summary

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

The NM_001353937.2(TTC3):​c.-1659T>C variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC3 NM_001353937.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

Genes affected

TTC3 (HGNC:12393): (tetratricopeptide repeat domain 3) Enables ubiquitin-protein transferase activity. Involved in protein K48-linked ubiquitination and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TTC3 (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=0.37554798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC3	NM_001330683.2	c.443T>C	p.Ile148Thr	missense_variant	6/46	ENST00000418766.6	NP_001317612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC3	ENST00000418766.6	c.443T>C	p.Ile148Thr	missense_variant	6/46	5	NM_001330683.2	ENSP00000403943.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000547

EpiControl AF: 0.00

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

Jun 23, 2023

The c.443T>C (p.I148T) alteration is located in exon 6 (coding exon 5) of the TTC3 gene. This alteration results from a T to C substitution at nucleotide position 443, causing the isoleucine (I) at amino acid position 148 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	.;T;T;T;T;T
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;.
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.0	.;.;M;.;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;D;N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.0	.;.;B;.;B;B
Vest4		0.87, 0.89, 0.95, 0.88
MutPred		0.45		Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);
MVP		0.70
MPC		0.12
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.22
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2073076999; hg19: chr21-38462549;