21-37121904-A-G

Variant summary

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

The NM_001330683.2(TTC3):c.988A>G(p.Lys330Glu) 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. 12/21 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)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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]

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=0.28153723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC3	NM_001330683.2	c.988A>G	p.Lys330Glu	missense_variant	12/46	ENST00000418766.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC3	ENST00000418766.6	c.988A>G	p.Lys330Glu	missense_variant	12/46	5	NM_001330683.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 20, 2022

The c.988A>G (p.K330E) alteration is located in exon 12 (coding exon 11) of the TTC3 gene. This alteration results from a A to G substitution at nucleotide position 988, causing the lysine (K) at amino acid position 330 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.075
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.50	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.011	D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		1.0, 0.89	.;.;.;D;P;D;D
Vest4		0.48, 0.33, 0.47, 0.50
MutPred		0.50		Loss of methylation at K330 (P = 0.0021);Loss of methylation at K330 (P = 0.0021);.;Loss of methylation at K330 (P = 0.0021);.;Loss of methylation at K330 (P = 0.0021);Loss of methylation at K330 (P = 0.0021);
MVP		0.62
MPC		0.34
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.37

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: rs997638652; hg19: chr21-38494204;