rs752973578

Variant names:

• chr21-37090245-C-T
• rs752973578
• NM_001330683.2:c.439C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001330683.2(TTC3):​c.439C>T​(p.Leu147Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,450,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10
• Publications: 1 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036340863).
• BP6: Variant 21-37090245-C-T is Benign according to our data. Variant chr21-37090245-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3463362.Status of the report is criteria_provided_single_submitter, 1 stars.

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.439C>T	p.Leu147Phe	missense	Exon 6 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001320703.2		c.505C>T	p.Leu169Phe	missense	Exon 6 of 47	NP_001307632.1
	TTC3	NM_001320704.2		c.439C>T	p.Leu147Phe	missense	Exon 6 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.439C>T	p.Leu147Phe	missense	Exon 6 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.439C>T	p.Leu147Phe	missense	Exon 5 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.439C>T	p.Leu147Phe	missense	Exon 6 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 245502 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1450012 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 721130

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.000115 AC: 5 AN: 43354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105298

Other (OTH) AF: 0.0000166 AC: 1 AN: 60070

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000499 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.62
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.055
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.30		Gain of MoRF binding (P = 0.2666)
MVP		0.36
MPC		0.096
ClinPred		0.058	T
GERP RS		4.6
Varity_R		0.038
gMVP		0.15
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs752973578; hg19: chr21-38462545; COSMIC: COSV61297415; COSMIC: COSV61297415;