5-160043127-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003314.3(TTC1):c.505-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,613,370 control chromosomes in the GnomAD database, including 104 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 0.0086 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (91 hom.)
• Consequence: TTC1 NM_003314.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003539
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.56

Genes affected

TTC1 (HGNC:12391): (tetratricopeptide repeat domain 1) This gene encodes a protein that belongs to the tetratrico peptide repeat superfamily of proteins. The encoded protein plays a role in protein-protein interactions, and binds to the Galpha subunit of G protein-coupled receptors to activate the Ras signaling pathway. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-160043127-T-C is Benign according to our data. Variant chr5-160043127-T-C is described in ClinVar as [Benign]. Clinvar id is 768047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00734 (10729/1461086) while in subpopulation SAS AF= 0.0186 (1602/85988). AF 95% confidence interval is 0.0179. There are 91 homozygotes in gnomad4_exome. There are 5565 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC1	NM_003314.3	c.505-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000231238.10
TTC1	NM_001282500.2	c.505-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC1	ENST00000231238.10	c.505-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003314.3	P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1311 AN: 152166 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00857 AC: 2148 AN: 250612 Hom.: 28 AF XY: 0.00902 AC XY: 1221 AN XY: 135438

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00734 AC: 10729 AN: 1461086 Hom.: 91 Cov.: 30 AF XY: 0.00766 AC XY: 5565 AN XY: 726816

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00578

Gnomad4 ASJ exome AF: 0.0232

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.00221

Gnomad4 NFE exome AF: 0.00625

Gnomad4 OTH exome AF: 0.00972

GnomAD4 genome AF: 0.00862 AC: 1312 AN: 152284 Hom.: 13 Cov.: 32 AF XY: 0.00814 AC XY: 606 AN XY: 74462

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00743 Hom.: 2

Bravo AF: 0.00919

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00784

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

Jun 28, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	10
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.020		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: rs77367863; hg19: chr5-159470134; COSMIC: COSV51464767; COSMIC: COSV51464767;