NM_001330683.2:c.205A>G

Variant names:

• chr21-37088213-A-G
• rs772950107
• NM_001330683.2:c.205A>G

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.205A>G​(p.Ile69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,474 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I69M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.958
• 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: 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=0.11569178).

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.205A>G	p.Ile69Val	missense	Exon 4 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001320703.2		c.271A>G	p.Ile91Val	missense	Exon 4 of 47	NP_001307632.1
	TTC3	NM_001320704.2		c.205A>G	p.Ile69Val	missense	Exon 4 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.205A>G	p.Ile69Val	missense	Exon 4 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.205A>G	p.Ile69Val	missense	Exon 3 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.205A>G	p.Ile69Val	missense	Exon 4 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248316 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456474 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724342

African (AFR) AF: 0.0000301 AC: 1 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4626

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109970

Other (OTH) AF: 0.0000333 AC: 2 AN: 60068

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.96
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.019
Sift	Benign	0.14	T
Sift4G	Benign	0.62	T
Polyphen		0.0050	B
Vest4		0.11
MutPred		0.26		Gain of ubiquitination at K73 (P = 0.0913)
MVP		0.34
MPC		0.075
ClinPred		0.031	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.093
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs772950107; hg19: chr21-38460513;