Genetic Variant TTC19:p.Phe2Val (chr17-15999852-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_017775.4(TTC19):c.4T>G(p.Phe2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Synonymous variant affecting the same amino acid position (i.e. F2F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTC19
NM_017775.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0600

Publications

0 publications found

Variant links:

Genes affected

TTC19 (HGNC:26006): (tetratricopeptide repeat domain 19) This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]

TTC19 links:

ZSWIM7 (HGNC:26993): (zinc finger SWIM-type containing 7) Predicted to enable zinc ion binding activity. Involved in double-strand break repair via homologous recombination and protein stabilization. Part of Shu complex. [provided by Alliance of Genome Resources, Apr 2022]

ZSWIM7 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: STRONG Submitted by: King Faisal Specialist Hospital and Research Center
ovarian dysgenesis 10
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
colorectal adenoma
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ZSWIM7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3684677).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017775.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC19	NM_017775.4	MANE Select	c.4T>G	p.Phe2Val	missense	Exon 1 of 10	NP_060245.3
TTC19	NM_001271420.2		c.-455T>G		5_prime_UTR	Exon 1 of 10	NP_001258349.1
ZSWIM7	NM_001042697.2	MANE Select	c.-258A>C		upstream_gene	N/A	NP_001036162.1	Q19AV6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC19	ENST00000261647.10	TSL:1 MANE Select	c.4T>G	p.Phe2Val	missense	Exon 1 of 10	ENSP00000261647.5	Q6DKK2
TTC19	ENST00000873205.1		c.4T>G	p.Phe2Val	missense	Exon 1 of 10	ENSP00000543264.1
TTC19	ENST00000873204.1		c.4T>G	p.Phe2Val	missense	Exon 1 of 10	ENSP00000543263.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1365294

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673364

African (AFR)

AF:

0.00

AC:

AN:

28870

American (AMR)

AF:

0.00

AC:

AN:

34066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23876

East Asian (EAS)

AF:

0.00

AC:

AN:

34162

South Asian (SAS)

AF:

0.00

AC:

AN:

77320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4326

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072180

Other (OTH)

AF:

0.00

AC:

AN:

56810

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0061

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.22

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.34

PhyloP100

-0.060

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.74

REVEL

Benign

0.20

Sift

Uncertain

0.021

Sift4G

Uncertain

0.036

Vest4

0.20

MutPred

0.27

Loss of helix (P = 0.079)

MVP

0.79

MPC

0.18

ClinPred

0.18

GERP RS

2.5

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.11

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over