dbSNP rs41275305: TTC1:p.Ala29Gly (chr5-160010614-C-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_003314.3(TTC1):c.86C>G(p.Ala29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00801 in 1,614,118 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.012 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 100 hom. )

Consequence

TTC1
NM_003314.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.172

Publications

7 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 -11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.65922 (below the threshold of 3.09). Trascript score misZ: 0.045692 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.0023789108).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1760/152298) while in subpopulation AFR AF = 0.0242 (1007/41560). AF 95% confidence interval is 0.023. There are 23 homozygotes in GnomAd4. There are 828 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC1	NM_003314.3 link	c.86C>G	p.Ala29Gly	missense_variant	Exon 2 of 8	ENST00000231238.10	NP_003305.1	Q99614
TTC1	NM_001282500.2 link	c.86C>G	p.Ala29Gly	missense_variant	Exon 2 of 8		NP_001269429.1	Q99614

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC1	ENST00000231238.10 link	c.86C>G	p.Ala29Gly	missense_variant	Exon 2 of 8	1	NM_003314.3	ENSP00000231238.4		Q99614

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1751

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0240

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00674

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:

0.0163

GnomAD2 exomes

AF:

0.00937

AC:

2356

AN:

251346

AF XY:

0.00964

show subpopulations

Gnomad AFR exome

AF:

0.0244

Gnomad AMR exome

AF:

0.00579

Gnomad ASJ exome

AF:

0.0223

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00742

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00765

AC:

11177

AN:

1461820

Hom.:

100

Cov.:

AF XY:

0.00790

AC XY:

5748

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0246

AC:

823

AN:

33478

American (AMR)

AF:

0.00644

AC:

288

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0232

AC:

606

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0187

AC:

1611

AN:

86244

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53420

Middle Eastern (MID)

AF:

0.0195

AC:

112

AN:

5734

European-Non Finnish (NFE)

AF:

0.00627

AC:

6976

AN:

1112002

Other (OTH)

AF:

0.0106

AC:

638

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

655

1310

1965

2620

3275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.0116

AC:

1760

AN:

152298

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

828

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0242

AC:

1007

AN:

41560

American (AMR)

AF:

0.00673

AC:

103

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0176

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00613

AC:

417

AN:

68034

Other (OTH)

AF:

0.0161

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00866

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.0102

AC:

1241

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.00789

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.9

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.059

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.68

.;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

0.17

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.012

Sift

Benign

0.089

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.020

B;B

Vest4

0.18

MPC

0.11

ClinPred

0.00067

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.063

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over