rs1281526371

Variant names:

• chr21-37087316-G-A
• rs1281526371
• NM_001330683.2:c.59G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330683.2(TTC3):​c.59G>A​(p.Cys20Tyr) 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. 16/22 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: 0.155
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039762735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330683.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC3	NM_001330683.2	MANE Select	c.59G>A	p.Cys20Tyr	missense	Exon 2 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001320703.2		c.125G>A	p.Cys42Tyr	missense	Exon 2 of 47	NP_001307632.1
	TTC3	NM_001320704.2		c.59G>A	p.Cys20Tyr	missense	Exon 2 of 47	NP_001307633.1	H7BZ57

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC3	ENST00000418766.6	TSL:5 MANE Select	c.59G>A	p.Cys20Tyr	missense	Exon 2 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.59G>A	p.Cys20Tyr	missense	Exon 1 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.59G>A	p.Cys20Tyr	missense	Exon 2 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.15
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.095
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.49		Loss of catalytic residue at H22 (P = 0.182)
MVP		0.18
MPC		0.15
ClinPred		0.039	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.20
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1281526371; hg19: chr21-38459616;