rs556511744

Variant names:

• chr21-37088235-C-G
• rs556511744
• NM_001330683.2:c.227C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-37088235-C-G
• chr21-37088235-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001353937.2(TTC3):​c.-1875C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TTC3 NM_001353937.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3051526).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353937.2. 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.227C>G	p.Ser76Cys	missense	Exon 4 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001353937.2		c.-1875C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 45	NP_001340866.1
	TTC3	NM_001320703.2		c.293C>G	p.Ser98Cys	missense	Exon 4 of 47	NP_001307632.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC3	ENST00000418766.6	TSL:5 MANE Select	c.227C>G	p.Ser76Cys	missense	Exon 4 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.227C>G	p.Ser76Cys	missense	Exon 3 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.227C>G	p.Ser76Cys	missense	Exon 4 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250976 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459820 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726160

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5056

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111250

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.061
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.047	D
Polyphen		0.91	P
Vest4		0.45
MutPred		0.36		Gain of ubiquitination at K73 (P = 0.0804)
MVP		0.78
MPC		0.26
ClinPred		0.74	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.28
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs556511744; hg19: chr21-38460535;