Genetic Variant TTC1:c.505-6T>C (chr5-160043127-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_003314.3(TTC1):c.505-6T>C variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00003539

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.56

Publications

3 publications found

Variant links:

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]

TTC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 768047.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 5565 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003314.3. 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
	TTC1	NM_003314.3	MANE Select	c.505-6T>C		splice_region intron	N/A	NP_003305.1	Q99614
	TTC1	NM_001282500.2		c.505-6T>C		splice_region intron	N/A	NP_001269429.1	Q99614

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTC1	ENST00000231238.10	TSL:1 MANE Select	c.505-6T>C	splice_region intron	N/A	ENSP00000231238.4	Q99614
TTC1	ENST00000522793.5	TSL:5	c.505-6T>C	splice_region intron	N/A	ENSP00000429225.1	Q99614
TTC1	ENST00000682719.1		c.505-6T>C	splice_region intron	N/A	ENSP00000507891.1	Q99614

Frequencies

GnomAD3 genomes

AF:

0.00862

AC:

1311

AN:

152166

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00857

AC:

2148

AN:

250612

AF XY:

0.00902

show subpopulations

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 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.:

Cov.:

AF XY:

0.00766

AC XY:

5565

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.0151

AC:

505

AN:

33470

American (AMR)

AF:

0.00578

AC:

258

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0232

AC:

605

AN:

26128

East Asian (EAS)

AF:

0.000126

AC:

AN:

39684

South Asian (SAS)

AF:

0.0186

AC:

1602

AN:

85988

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53408

Middle Eastern (MID)

AF:

0.0186

AC:

107

AN:

5768

European-Non Finnish (NFE)

AF:

0.00625

AC:

6942

AN:

1111606

Other (OTH)

AF:

0.00972

AC:

587

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

458

915

1373

1830

2288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

280

560

840

1120

1400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00862

AC:

1312

AN:

152284

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

606

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0139

AC:

577

AN:

41550

American (AMR)

AF:

0.00601

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0176

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00613

AC:

417

AN:

68028

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

196

261

326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00760

Hom.:

Bravo

AF:

0.00919

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.00784

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

2.6

PromoterAI

-0.0031

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over