21-37095344-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001330683.2(TTC3):c.688-6T>C variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000357 in 1,592,128 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: TTC3 NM_001330683.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01335
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.62

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 21-37095344-T-C is Benign according to our data. Variant chr21-37095344-T-C is described in ClinVar as [Benign]. Clinvar id is 769126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC3	NM_001330683.2	c.688-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000418766.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC3	ENST00000418766.6	c.688-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330683.2	P2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000496 AC: 117 AN: 235656 Hom.: 1 AF XY: 0.000447 AC XY: 57 AN XY: 127490

Gnomad AFR exome AF: 0.00550

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000535

GnomAD4 exome AF: 0.000240 AC: 346 AN: 1439872 Hom.: 1 Cov.: 29 AF XY: 0.000234 AC XY: 168 AN XY: 716480

Gnomad4 AFR exome AF: 0.00655

Gnomad4 AMR exome AF: 0.000583

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000483

Gnomad4 FIN exome AF: 0.000301

Gnomad4 NFE exome AF: 0.0000290

Gnomad4 OTH exome AF: 0.000725

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152256 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74452

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000573 Hom.: 1

Bravo AF: 0.00170

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.40
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

Publications

LitVar

Other links and lift over

dbSNP: rs143762501; hg19: chr21-38467644;