Genetic Variant TTC9:p.Pro94Leu (chr14-70642410-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015351.2(TTC9):c.281C>T(p.Pro94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,597,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TTC9
NM_015351.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.72

Publications

0 publications found

Variant links:

Genes affected

TTC9 (HGNC:20267): (tetratricopeptide repeat domain 9) This gene encodes a protein that contains three tetratricopeptide repeats. The gene has been shown to be hormonally regulated in breast cancer cells and may play a role in cancer cell invasion and metastasis. [provided by RefSeq, Mar 2009]

TTC9 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06531197).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015351.2. 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
	TTC9	NM_015351.2	MANE Select	c.281C>T	p.Pro94Leu	missense	Exon 1 of 3	NP_056166.1	Q92623

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC9	ENST00000256367.3	TSL:1 MANE Select	c.281C>T	p.Pro94Leu	missense	Exon 1 of 3	ENSP00000256367.2	Q92623
	TTC9	ENST00000928641.1		c.281C>T	p.Pro94Leu	missense	Exon 1 of 2	ENSP00000598700.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445196

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717642

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32464

American (AMR)

AF:

0.00

AC:

AN:

42938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25646

East Asian (EAS)

AF:

0.00

AC:

AN:

38694

South Asian (SAS)

AF:

0.00

AC:

AN:

83674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105310

Other (OTH)

AF:

0.00

AC:

AN:

59658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.53

M_CAP

Benign

0.015

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.39

PhyloP100

1.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.27

REVEL

Benign

0.022

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.075

MutPred

0.32

Gain of catalytic residue at P92 (P = 9e-04)

MVP

0.18

MPC

0.63

ClinPred

0.17

GERP RS

2.4

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.056

gMVP

0.10

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over