NM_001330683.2:c.5156C>T

Variant names:

• chr21-37192152-C-T
• rs746595632
• NM_001330683.2:c.5156C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330683.2(TTC3):​c.5156C>T​(p.Ser1719Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• 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]

TTC3-AS1 (HGNC:40595): (TTC3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1538994).

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.5156C>T	p.Ser1719Phe	missense	Exon 41 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001320703.2		c.5276C>T	p.Ser1759Phe	missense	Exon 42 of 47	NP_001307632.1
	TTC3	NM_001320704.2		c.5210C>T	p.Ser1737Phe	missense	Exon 42 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.5156C>T	p.Ser1719Phe	missense	Exon 41 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.5156C>T	p.Ser1719Phe	missense	Exon 40 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.5156C>T	p.Ser1719Phe	missense	Exon 41 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249638 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459076 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725562

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.0000901 AC: 4 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110576

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.062
Sift	Benign	0.37	T
Sift4G	Uncertain	0.039	D
Polyphen		0.48	P
Vest4		0.42
MutPred		0.26		Loss of disorder (P = 0.0053)
MVP		0.43
MPC		0.21
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.098
gMVP		0.27
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: rs746595632; hg19: chr21-38564453; COSMIC: COSV61286126; COSMIC: COSV61286126;