chr21-37091365-G-A

Position:

• chr21-37091365-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001330683.2(TTC3):​c.553G>A​(p.Gly185Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC3	NM_001330683.2	c.553G>A	p.Gly185Arg	missense_variant	7/46	ENST00000418766.6	NP_001317612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC3	ENST00000418766.6	c.553G>A	p.Gly185Arg	missense_variant	7/46	5	NM_001330683.2	ENSP00000403943.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

May 26, 2023

The c.553G>A (p.G185R) alteration is located in exon 7 (coding exon 6) of the TTC3 gene. This alteration results from a G to A substitution at nucleotide position 553, causing the glycine (G) at amino acid position 185 to be replaced by an arginine (R). 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	0.28
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	.;T;.;T;T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T;D;.;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	2.0	.;.;.;M;.;M;M
MutationTaster	Benign	0.92	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.054	T;T;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;D;T;T
Polyphen		1.0	.;.;.;D;.;D;D
Vest4		0.47, 0.43, 0.59, 0.47
MutPred		0.63		Gain of catalytic residue at G185 (P = 0.0738);Gain of catalytic residue at G185 (P = 0.0738);.;Gain of catalytic residue at G185 (P = 0.0738);Gain of catalytic residue at G185 (P = 0.0738);Gain of catalytic residue at G185 (P = 0.0738);Gain of catalytic residue at G185 (P = 0.0738);
MVP		0.69
MPC		0.51
ClinPred		0.87	D
GERP RS		6.1
Varity_R		0.16
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38463665;