Genetic Variant TTC3:p.Ser76Phe (chr21-37088235-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001353937.2(TTC3):c.-1875C>T 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 0.00000993 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TTC3
NM_001353937.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

Publications

1 publications found

Variant links:

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]

TTC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14971945).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC3	NM_001330683.2	MANE Select	c.227C>T	p.Ser76Phe	missense	Exon 4 of 46	NP_001317612.1	P53804-1
TTC3	NM_001353937.2		c.-1875C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 45	NP_001340866.1
TTC3	NM_001320703.2		c.293C>T	p.Ser98Phe	missense	Exon 4 of 47	NP_001307632.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC3	ENST00000418766.6	TSL:5 MANE Select	c.227C>T	p.Ser76Phe	missense	Exon 4 of 46	ENSP00000403943.2	P53804-1
TTC3	ENST00000354749.6	TSL:1	c.227C>T	p.Ser76Phe	missense	Exon 3 of 45	ENSP00000346791.2	P53804-1
TTC3	ENST00000399017.6	TSL:1	c.227C>T	p.Ser76Phe	missense	Exon 4 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250976

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459820

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726160

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5056

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111250

Other (OTH)

AF:

0.00

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000723

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.84

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

PhyloP100

3.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

REVEL

Benign

0.060

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.059

Polyphen

0.48

Vest4

0.45

MVP

0.74

MPC

0.21

ClinPred

0.37

GERP RS

3.8

Varity_R

0.14

gMVP

0.28

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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