GeneBe

4-146874765-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_031956.4(TTC29):​c.750C>G​(p.Tyr250*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000686 in 1,457,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TTC29
NM_031956.4 stop_gained

Scores

4
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.37
Variant links:
Genes affected
TTC29 (HGNC:29936): (tetratricopeptide repeat domain 29) Involved in cilium movement and cilium organization. Located in sperm flagellum. Implicated in spermatogenic failure 42. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTC29NM_031956.4 linkc.750C>G p.Tyr250* stop_gained Exon 7 of 13 ENST00000325106.9 NP_114162.2 Q8NA56-1A0A140VK62Q8TC83

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTC29ENST00000325106.9 linkc.750C>G p.Tyr250* stop_gained Exon 7 of 13 1 NM_031956.4 ENSP00000316740.4 Q8NA56-1
TTC29ENST00000508306.5 linkn.750C>G non_coding_transcript_exon_variant Exon 7 of 14 1 ENSP00000422648.1 E7EQZ6
TTC29ENST00000513335.5 linkc.828C>G p.Tyr276* stop_gained Exon 8 of 14 2 ENSP00000423505.1 G5E9Z5
TTC29ENST00000504425.5 linkc.750C>G p.Tyr250* stop_gained Exon 7 of 13 5 ENSP00000425778.1 E7EQ14

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457180
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
724584
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33406
American (AMR)
AF:
0.00
AC:
0
AN:
44248
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26062
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39492
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85608
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53202
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4912
European-Non Finnish (NFE)
AF:
9.01e-7
AC:
1
AN:
1110116
Other (OTH)
AF:
0.00
AC:
0
AN:
60134
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Uncertain
0.95
D
PhyloP100
4.4
Vest4
0.32
GERP RS
5.9
Mutation Taster
=0/200
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.27
Position offset: -49

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763399136; hg19: chr4-147795917; API